Method and system for intravesicular delivery of therapeutic agents

ABSTRACT

A therapeutic agent delivery implant for implantation into a patient&#39;s body comprises a resilient or flexible, at least partially hydrophobic reticulated elastomeric support scaffold; and a hydrophilic coating arranged on said scaffold, wherein said coating contains one or more therapeutic agents for release within the patient. Optionally the coating can contain microspheres or enzymes. In a preferred embodiment, the scaffold comprises a hydrophobic polyurethane, the coating comprises a hydrophilic polyurethane, and the implant has a hemispherical, bullet, football, cylindrical, spherical, or irregular shape. The implant can be delivered through a rigid or flexible delivery instrument that deploys the implant at a desirable site, whereby the implant expands to a size and shape substantially similar to its size and shape before insertion.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application is based upon co-pending, commonly assigned,U.S. provisional patent application Ser. No. 60/420,180, filed Oct. 22,2002, which is incorporated herein in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to methods and devices for theintravesicular delivery of therapeutically active agents or materials tothe bladder or other privileged mammalian sites for local or systemicuse. Preferred embodiments of the invention relate to delivery oftherapeutically active substances to the human organs such as thebladder to provide local or systemic therapeutic effects.

BACKGROUND OF THE INVENTION

[0003] Orally ingested drugs are subject to four possible fates in amammal: First, the drug can be absorbed through the mucosa of thestomach or small intestine and delivered to a vein unaltered to be latermetabolized in the liver or other organ to more soluble forms that beutilized by their target organ or metabolized to a form for elimination.Second, the drug can be metabolized in the proximal gastrointestinaltract without further action in the liver. Third, the drug can bemetabolized both by the proximal gastrointestinal tract and by theliver. And fourth, the drug can remain unabsorbed or unprocessed in thegastrointestinal tract, to be passed in much the same state as it wasswallowed. The nature of the metabolism pathway of a drug is often quitesignificant since drug metabolites may have very different directeffects and side effects than does the parent drug.

[0004] Alternative routes such as subcutaneous or intravenous injectionare unattractive because the risk of infection and the pain associatedwith injections. Additionally, used needles and syringes must bedisposed of properly in a biohazard container which can cause clutterfor the user. When a patient or relatively untrained person performsinjections, the risk of injecting into a blood vessel increases. If somedrugs are injected into the bloodstream, too much of that drug issystemically active and can cause serious effects of even death.Injections themselves cause localized trauma, and often the injectedsubstance can cause localized effects at an injection site; therefore,if repeated injections are necessary, the site of injection needs to bevaried to prevent too much damage to the one site. However, patients mayfind this to be uncomfortable since they are traumatizing a new area oftheir body each day. This discomfort can lead to non-compliance on thepart of the patient.

[0005] Insertion into a patient's oral cavity or body cavities, such aswith anal, vaginal, or urethral suppositories or pessaries, has alsobeen used for drug delivery. The problem with such insertion hasgenerally been getting the desired substance across the mucous membraneand into the bloodstream without damage to the delivery site. Also, timedelay and accessibility have been problems. Additionally, many peopleare uncomfortable talking about inserting items into body cavities, evenfor therapeutic purposes.

[0006] Transdermal drug delivery has been tried over the years. One ofthe main problems is transporting the substance across the skin layersand into the bloodstream. Chemical carriers such as DMSO have been triedwith some limited success. Also, the use of electrical impulse(electrophoresis) and sound waves (sonophoresis) have been used to drivea drug internally. However, many drugs are just molecularly too large topass through the dermis. Further, many of the drugs used in transdermaldrug delivery systems cause skin irritation which increases the risk ofnon-compliance by the patient.

[0007] Bladder cancers are usually treated with a series of infusions,lasting from one to several months, of anti-cancer drugs through theurethra. These infusions take about one to two hours to occur andrequire a minor operative procedure. The infused chemotherapeutics arethen prevented from being released from the bladder for a period ofapproximately one hour. After the treatment, the bladder is usuallysignificantly irritated.

[0008] Chronic urinary tract infections are often hard to treat sincethey often respond marginally to oral antibiotics. A urinary tractinfection can also spread to the blood stream, causing life-threateningsepticemia. In patients that are immunologically compromised orparalyzed, due to a spinal cord injury, for example, urinary tractinfections are a major problem since oral antibiotics do not function asa prophylactic to the infection. Accordingly, patients exhibiting theseconditions are treated with either oral or intravenous antibiotics. Suchpatients often are subject to catheterization multiple times a day toremove urine from the bladder so that monthly catheterization forreplacement of a drug delivery implant would not be unduly burdensome tothe patient, especially as paralyzed patients are often desensate.Economic benefits may also accrue attributable to a reduced need forintravenous antibiotics, hospitalization, and invasive procedures totreat urinary tract infections.

[0009] Accordingly it would be desirable to provide a drug deliverysystem which avoids one or more of the drawbacks mentioned above withinjection, insertion or transdermal delivery or for the treatment ofbladder cancer or urinary tract infections.

OBJECTS OF THE INVENTION

[0010] It is an object of the invention to provide methods and devicesfor the intravesicular delivery of therapeutic agents or materials tothe bladder or other privileged mammalian sites for local or systemicuse.

[0011] It is also an object of the invention to provide implants fordelivery of therapeutic agents or materials to human organs such as thebladder to provide local or systemic therapeutic effects.

[0012] It is a further object of the invention to provide an implant fortreatment of bladder cancer by intravesicular delivery.

[0013] It is yet further object of the invention to provide an implantfor delivering therapeutic agents or materials which comprises aresilient or flexible, at least partially hydrophic reticulatedelastomeric support scaffold and one or more therapeutically activeagents or materials secured to or supported by the scaffold, for releasewithin a patient.

[0014] It is yet further object of the invention to provide an implantfor delivery of therapeutically active agents or ingredients whichcomprise a resilient or flexible, at least partially hydropholicreticulated elastomeric support scaffold and a coating arranged on saidscaffold, wherein said coating contains one or more therapeuticallyactive agents or materials for release within a patient.

[0015] It is a yet further object of the invention to provide a methodfor delivering an implant with therapeutically active agents ormaterials to a patient, which comprises the steps of:

[0016] (a) collapsing and compressing an implant comprising a resilientor flexible, at least partially hydrophobic reticulated elastomericsupport scaffold and one or more therapeutically active agents ormaterials;

[0017] (b) inserting the collapsed and compressed implant into adelivery instrument;

[0018] (c) advancing the delivery instrument into a patient;

[0019] (d) deploying the implant at a desired site; whereby the implantwill recover substantially to its original shape and size afterdeployment; and

[0020] (e) thereafter withdrawing the delivery instrument.

[0021] It is a yet further object of the invention to provide a methodof treating a urinary tract condition or disease, which comprises thesteps of:

[0022] (a) compressing and collapsing an implant comprising a resilientor flexible, at least partially hydrophobic reticulated support scaffoldand one or more therapeutically active agents or materials;

[0023] (b) inserting the collapsed implant into a delivery instrument;

[0024] (c) advancing the delivery instrument through the patient'surethra;

[0025] (d) deploying the implant at a desired site within the patient'sbladder, whereby the implant will recover substantially to its originalshape and size after deployment; and

[0026] (e) withdrawing the delivery instrument.

[0027] These and other objects of the invention will become moreapparent from the discussion below.

SUMMARY OF THE INVENTION

[0028] In accordance with the invention, a therapeutic agent implant forimplantation to a mammalian site is provided. The implant comprises aresilient or flexible, at least partially hydrophobic reticulatedelastomeric support scaffold and one or more therapeutic agents securedto and/or supported by the scaffold for release at the mammalian site.The therapeutic agent delivery implant is insertable into a mammalianbladder or other suitable site via the urethra and is locatable withinthe bladder. Optionally the implant is out of stimulative contact withthe trigone during the normal daily host routine. Preferably, thetherapeutic agent delivery implant remains stable and fixed against themucous membrane of the bladder away from the trigone. Alternatively, itcan float clear of the trigone.

[0029] In preferred embodiments of the invention, the implants areintended to have varied shapes and may have a cross-sectional area lessthan, equal to, or greater than the effective cross-sectional area ofthe bladder, to the extent that they may move within the bladder. In oneembodiment of the invention the therapeutic agent delivery implant canbe positioned in the dome of the bladder and permit flow of urinethrough the therapeutic agent delivery implant material. The therapeuticagent delivery implant of this embodiment can optionally be shaped toengage and lodge against the bladder inner wall and may be configured,sized, and prestressed to have a cross-sectional area in excess of theanticipated maximum cross-sectional area of the intended recipientbladder. Preferred shapes include cylindrical, football, bullet, andsphere. Preferably the therapeutic agent delivery implant is biodurable,porous, reticulated, and compressibly elastomeric and demonstratesresilient delivery.

[0030] In another embodiment of the invention, a method of delivering animplant to a mammalian site comprises the steps of:

[0031] (a) compressing and collapsing and loading into a deliveryinstrument such as a cannula, trocar, catheter, or any type of minimallyinvasive rigid or flexible instrument, optionally one incorporatingvisualization or electromechanics, such as a cystoscope, laproscope,arthroscope, or endoscope, or the like, a resiliently compressiblereticulated therapeutic agent delivery implant having an expandedconfiguration when deployed;

[0032] (b) advancing the loaded delivery instrument through a mammalianurethra to access the bladder;

[0033] (c) deploying the drug delivery implant through the deliveryinstrument into the bladder, whereby the implant will recoversubstantially to its original shape and size after deployment; and

[0034] (d) withdrawing the delivery instrument, leaving the drugdelivery implant in the bladder.

[0035] In yet another embodiment of the invention a therapeutic agentdelivery implant is positioned at or adjacent to any desired site withina patient's body. The implant could be delivered in a non-compressedstate, but preferably it is compressed and then loaded into a suitable,flexible or rigid, delivery instrument, such as a cannula, trocar,catheter, or any type of minimally invasive rigid or flexibleinstrument, optionally one incorporating visualization orelectromechanics, such as a cystoscope, laproscope, arthroscope, orendoscope, or the like, the distal portion of the delivery instrument isadvanced to a position at or adjacent to a target site, such as anorgan, and the implant is deployed.

[0036] In a further embodiment of the invention, after a sufficient timeor a sufficient amount of therapeutic agent delivery or therapy, torecover the therapeutic agent delivery implant the implant is pulledinto a flexible or rigid removal instrument, such as a cannula, trocar,catheter, or any type of minimally invasive rigid or flexibleinstrument, optionally one incorporating visualization orelectromechanics, such as a cystoscope, laproscope, arthroscope, orendoscope, or the like, that has been inserted into the patient's body,for example, into the urethra. More specifically, the removal instrumentis inserted into the urethra, and the drug delivery implant is removedfrom the bladder with the removal instrument. The removal instrumentoptionally includes a fiberoptic device for viewing the drug deliveryimplant. In addition, a gripping implement may be optionally deployedthrough the removal instrument to grip the drug delivery implant anddraw it into the removal instrument. Further, the implant may have aprojection or feature that facilitates gripping by or connection to theremoval instrument.

[0037] In yet further embodiment of the invention, a therapeutic agentdelivery device comprises:

[0038] an at least partially hydrophobic, reticulated elastomericsupport scaffold and

[0039] at least one therapeutic agent secured to or supported by thescaffold or incorporated into a coating that is supported by thescaffold

[0040] and is implanted in a patient's body, within the bladder orelsewhere. It can be delivered through or by means of one of thedelivery instruments described above, and it can be removed through orby means of one of the removal instruments described above.

BRIEF DESCRIPTION OF THE DRAWINGS

[0041] One or more embodiments of the invention and of making and usingthe invention, as well as the best mode contemplated of carrying out theinvention, are described in detail below, by way of example, withreference to the accompanying drawings, in which:

[0042]FIG. 1 is a schematic cross-sectional view of a human bladder;

[0043]FIG. 2 is a lateral cross-sectional view of an implant fordelivering therapeutic agents according to one embodiment of theinvention;

[0044]FIG. 3 is an underneath plan view of the therapeutic agentdelivery implant shown in FIG. 2;

[0045]FIG. 4 is a partial cross-sectional view of a modified embodimentof the therapeutic agent delivery implant shown in FIG. 2 afterimplantation into the bladder shown in FIG. 1;

[0046]FIG. 5 is a lateral elevational view of another embodiment ofimplant;

[0047]FIG. 6 is a lateral elevational view of a second embodiment of atherapeutic agent delivery implant according to the invention;

[0048]FIG. 7 is a plan view of a spherical embodiment of a therapeuticagent delivery implant according to the invention;

[0049]FIG. 8 is a lateral elevational view of a fusiform or “football”embodiment of therapeutic agent delivery implant according to theinvention;

[0050]FIG. 9 is a schematic view of the implant of FIG. 8 floating inthe bladder;

[0051]FIG. 10 is a lateral elevational view of a bullet-shapedembodiment of therapeutic agent delivery implant according to theinvention;

[0052]FIG. 11 is a lateral elevational view of a cylindrical embodimentof therapeutic agent delivery implant according to the invention;

[0053]FIG. 12 is a plan view of a biconcave disc-shaped biologic agentdelivery implant according to the invention;

[0054]FIG. 13 is cross-sectional view on the line 13-13 of FIG. 12;

[0055]FIG. 14 is a lateral elevational view of a spaghetti strandbiologic agent delivery implant according to the invention;

[0056]FIG. 15 is a lateral elevational view of a biologic agent deliveryimplant according to the invention having a configuration like that of amophead;

[0057]FIG. 16 is a plan view of one implant introducer instrument havingthe form of a rigid cystoscope;

[0058]FIG. 17 is a plan view of another implant introducer instrumenthaving the form of a flexible cystoscope;

[0059]FIG. 18 is a plan view of a further implant introducer instrumenthaving the form of a plunger-equipped catheter;

[0060]FIG. 19 is a plan view of a still further implant introducerinstrument also in the form of a forceps-equipped catheter;

[0061]FIG. 20 is an enlarged partly sectional view of the tip of amodified catheter such as that shown in FIG. 18; and

[0062]FIG. 21 is a schematic sectional view of a portion of a humanbladder inner wall.

DETAILED DESCRIPTION OF THE INVENTION

[0063] The invention can perhaps be understood better from the drawings.As shown in FIG. 1, the urinary bladder 10 is a hollow, muscular organlocated in the pelvic cavity. The common functions of the bladder areaccommodation of urine, storage of urine, maintenance of urinecomposition and facilitation of voiding at appropriate time intervals.When the bladder 10 is empty, the inner walls 12 are retracted intofolds 14 defining a relatively small bladder volume. As the bladder 10fills with urine, it distends, the inner walls 12 extend and becomesmooth, and the superior surfaces 18 of the inner walls expand upwardlyinto distended volume, shown in broken lines 20, with the expanded wallsdefining a relatively larger bladder volume. A typical human bladder hasthe capacity to hold up to approximately 600 milliliters of urine or, insome cases, as much as about one liter. The desire to micturate orurinate usually occurs when the bladder contains approximately 150milliliters of urine.

[0064] The inner floor of bladder 10 includes a triangular area calledthe trigone 22, which has openings at each of its three angles. Theposterior aspect of the trigone 22 is the base of the triangle where theureters 24 and 26, bringing urine from the kidneys, empty into bladder10 through openings 25 and 27 at the two posterior corners of trigone22. The anterior aspect of the trigone 22 at the apex of the triangle isa funnel-shaped extension called the neck 28 of bladder 10, which opensinto the urethra 30. The trigone 22 generally remains fixed in positionwhile bladder 10 is distending and contracting.

[0065] The wall of bladder 10 has four layers. An innermost layer calledthe mucous coat or urothelium 32 has a thickness which changes asbladder 10 expands and contracts, becoming thinner as bladder 10expands. A second layer is the submucous coat 34 which containsconnective tissue and elastic fibers. A third layer is the muscle coat36 which is made mostly of smooth muscle having fibers interlaced toform what is known as the detrusor muscle 40. The outer layer is theserous layer and is only found on the superior portion or dome 38 of thebladder 10.

[0066] The portion of the detrusor muscle 40 that surrounds the neck ofthe bladder 28 forms the internal urethral sphincter which controlsmicturition. The internal urethral sphincter sustains a contracted stateto prevent the bladder from emptying until the pressure of urineaccumulating within the bladder reaches a threshold level. When thethreshold level is reached, the parasympathetic nervous system istriggered to intermittently relax the detrusor muscle 40, causing asensation of urgency. The external urethral sphincter, which is undervoluntary control, must be relaxed for micturition to take place.

[0067] Many factors can provide the sensation of a full bladder and theneed for micturition, including, for example, distention of the bladder,usually due to urine or in some instances gas, irritation of the liningof the bladder and the viscosity of the bladder contents, namely, urine.The bladder may generate a sensation of being full, even when it is not,if abnormally viscous urine is present.

[0068] Consequently, any objects, materials, or substances introducedinto bladder 10 for therapeutic purposes should avoid inducing any ofthese conditions or they may trigger unacceptable micturition and mayeven be voided before they can have their desired therapeutic effects.Additionally, trigone 22 is extremely sensitive to contact with foreignobjects so that any object or material introduced into the bladdershould also be designed to have minimal or no contact with trigone 22.Further, any implant should preferably be designed to avoid or minimizeprolonged contact with the trigone, especially to avoid stimulation orobstruction of urine flow or the bladder neck. In addition,non-selective or selective sympathetic or parasympathetic receptorblocking gents can be administrated, examples of which agents includelidocaine or similar derivatives, capaciacin, and capaciacin-likeagents. These agents are intrinsically incorporated either initially orlater to induce bladder tolerance to an implant for the duration of the“implant” residence in the bladder. In addition, such an agent can beused to treat a given physiological condition.

[0069] The innermost layer of the bladder wall 12, urothelium 32,functions physiologically in the accommodation and storage of urine,maintenance of urine composition, facilitation of voiding andcontainment of potential toxins within the bladder to prevent theirsystemic absorption. The urothelium has three cellular zones: a basallayer, which is the outermost layer with respect to the interior of thebladder and contains cells which are mostly germinal in nature; anintermediate cell layer; and an innermost layer which lines the lumen ofbladder 10 and comprises epithelial umbrella cells. The luminal surfacesof the umbrella cells are coated with a layer of glycosaminoglycans.This anatomy is illustrated in more detail in FIG. 16 and may be betterunderstood from the description of that figure set forth below.

[0070] The permeability of the bladder wall 12 to chemical andbiological substances such as toxins, bacteria and therapeutic agents isbelieved to be dependent upon the permeability of the urothelium 32. Theumbrella cells in the urothelium act as a primary urine-plasma barrierto keep substances within the urine from re-entering the circulatorysystem, even under extremely high concentration gradients between theplasma and the urine. Some factors affecting bladder wall permeabilityinclude: passive diffusion, osmotically driven diffusion, activetransport, and the inertness of the membrane to the solutes to which itis exposed. When the device of the invention is inserted into thebladder but is intended to treat conditions or infections within thepatient but external to the bladder, such as osteomylitis, it isadvantageous to add physiologically acceptable membrane solubilizerssuch as protemine sulfate or polyethylene gycol to the therapeuticagents or the carriers to cause transient permeability andpermissiveness of the mucosa to enter its submucosa.

[0071] The embodiment of the invention shown in FIGS. 2 to 5 provides anapparatus and method for delivery to privileged mammalian sites such asbladder 10 of therapeutic agents, including not only activepharmaceutical substances such as drugs but agents such as enzymes,antibodies, cells, DNA, RNA, viruses, bacteria, vectors and the like.The term therapeutic agents is used herein to embrace all suchtherapeutic agents, unless the context clearly indicates otherwise. Amore detailed listing of useful therapeutic agents is set forth below.

[0072] Implant

[0073] The apparatus and method of the invention employ a novel implantfor delivering drugs and other biologic agents, as a carrier for a drugor other therapeutic agents. An implant can have any of a wide range ofshapes and configurations, according to the particular circumstances ofa given application, including cylindrical, football, bullet, spherical,or an irregular shape, as shown below. Illustrated in FIG. 2 is anembodiment of an implant 42 which is suitable for delivery oftherapeutic agents into the urinary bladder 10. The delivered one ormore therapeutic agents may be for use locally or systemically or may bedelivered to the bladder for systemic transport to other in vivoapplication sites as will be described in more detail hereinafter.

[0074] Pursuant to an embodiment of the invention, implant 42 is a novelarticle or device which comprises a drug-bearing porous, biodurable,reticulated elastomeric matrix designed to be inserted into the bladderthrough a cannula, catheter, trocar, cystoscope, or other suitableintroducer instrument. Preferred embodiments of implant 42 comprise aone-piece flexible thin-walled, shell-like hollow body, such as thesuperior hemisphere of a plastic ball, which hollow body is collapsibleto a compact configuration for accommodation in the introducerinstrument and is expansible to an expanded or extended workingconfiguration in situ. To these ends, implant 42 may be fabricated of aresilient or flexible porous material, preferably a resilient andflexible porous material, for example, a resilient foam, especially, forexample, a reticulated polyurethane foam coated on its pore surfaceswith a drug-bearing material such as a partially hydrophilic foam.

[0075] The particular embodiment of implant 42 illustrated in FIG. 2 hasa domical, optionally hemispherical, shape, to occupy much or most ofthe space within bladder dome 38 when bladder 10 is substantially empty,and has a diameter 44 and a height 46. Where the domical shape is a truehemisphere, or approximation thereof, which is a functionally usefulshape that is also convenient to manufacture, height 46 is the radius ofthe sphere and therefore is equal to one half of diameter 44. However,different portions of a sphere, or other shape may be employed, for thedomical shape of implant 42, if desired, and in particular, height 46may be rather less than half of diameter 44, for example, up to about 20percent less. Such a shallower shape for implant 42 is contemplated asbeing less likely to contact sensitive trigone 22 when properlyoriented.

[0076] As shown in FIG. 3, implant 42, being hemispherical, is circularin cross-section. However, many modifications may be made to theparticular shape and configuration of implant 42, as will be, or willbecome, apparent to those skilled in the art, and as are describedherein. In particular, the domical shape of implant 42 may have othersmoothly curved configurations than part-spherical, and may for example,be a partial ellipsoid or a partial paraboloid.

[0077] Articles fabricated of foam and other porous materials may beconsidered to have both external and internal surfaces. The termexternal surface is used herein to reference the outer surface of thearticle itself, while the term internal surface or internal surfaces isused to reference the surfaces of the pores or other openings in theporous material. Thus, for example, a cube of unit length per side, ofan open-celled foam having some tens of pores per linear side, has sixflat square external surfaces, and a complex, extended array of internalsurfaces permeating the whole body of the cube. While the total externalsurface area will be six units, the internal surface area may be muchhigher, some tens or even hundreds of units depending upon the porosityand particular microstructure of the foam material. A domical shape, asdescribed above, is a useful shape for implant 42 providing an extendedexternal surface area in the upper portion of a site such as bladder 10,away from the sensitive trigone 22.

[0078] Implant 42, as illustrated, has a peripheral sidewall skirtportion 48 and an upper portion 50. Preferably, diameter 44 is selectedto be somewhat larger than the largest diameter or girth of the targetbladder 10 so that the outer skirt portion 48 is resiliently urgedoutwardly, preferably with an appropriately gentle force, againstbladder 10's inner walls 12, by the resilience of the implant material.Such outward urging can help locate implant 42 at a suitable position orpositions within bladder 10, especially a position reducing orminimizing risk of contact with the trigone 22. Thus, for example, skirtportion 48 is preferably positioned to engage and exert a modest outwardforce against a sidewall portion of inner walls 12, referring to anupright bladder position and a preferred orientation of implant 42. Itshould be recognized that the implant may be another shape and/or size,as discussed below, and that the implant may float easily within bladder10.

[0079] Height 46 is preferably chosen to enable implant 42 to remain inthe above-described preferred position when the bladder 10 contracts toits smallest configuration as it is voided. Preferably height 46 is suchthat little downward pressure is exerted on the upper portion 50 ofimplant 42 by bladder dome 38 when the bladder contracts, to avoiddisplacing implant 42. However, light pressure from bladder dome 38 onimplant 42 may be acceptable. To this end, implant 42 may, if desired,be formed of a readily flexible material, at least, in its upper portion50 to accommodate the contractions of bladder dome 38.

[0080] In the domical embodiment illustrated, the external surfaces ofimplant 42 comprise a concave inner surface 52 and a convex outersurface 54. As shown in FIG. 2, inner surface 52 and outer surface 54are substantially equidistant from one another throughout their extent,so that implant 42 has a substantially uniform thickness between the twosurfaces 52 and 54, subject to manufacturing and microstructuralvariations. However, such uniformity is merely one embodiment of theinvention, and implant 42 may otherwise have uneven thickness.

[0081] Preferably the geometry and materials of an implant such asimplant 42 are selected to provide an implant which can meet therequirements of being capable of supporting a useful quantity of atherapeutic agent to be delivered; of being collapsible, while bearingthe useful quantity of therapeutic agent, into an introducer instrumentfor implantation to the intended site; of being deployable at thedesired site in a manner which permits access of bodily fluids todiffuse the therapeutic agent from the implant and which does notinterfere with normal bodily functions; and of being able tosubstantially recover its shape and size upon deployment. Preferably,when utilized as a urinary bladder implant, an implant such as implant42, in its deployed configuration, has an extended surface area on whichthe therapeutic agent or agents are supported for release and does notsignificantly affect the available urinary volume of the bladder.Preferably, also, an implant such as implant 42 is deployed to releasethe therapeutic agent in the vicinity of the biological structures thatcan utilize it or receive it for transport elsewhere, for example, inthe vicinity of bladder inner walls 12, especially dome 22 as in thecase of implant 42.

[0082] A domical configuration of implant 42 such as that illustrated inFIG. 2 is intended to fulfil some or all of these objectives whenembodied in a suitable material such as the polymeric foam and otherporous materials described herein. In particular, a domical shape, orequivalent cap-like or tent-like shape, which converges upwardly towarda center from an open or preferably closed loop periphery, embodied in asheet-like porous material, provides a device which can be implanted tobody sites such as the urinary bladder by collapsing the implant into asmall, longitudinal volume. Such a device can extend, or be extendedwithin the bodily site to have a substantial external surface area forexposure of the material of the implant to, and permeation of thematerial by, bodily fluids, or possibly gases. Other shapes canaccomplish this as well.

[0083] The diameter 44 and the height 46 of implant 42 can be varied toprovide implants 42 of different sizes to be accommodated withinbladders of differing sizes. Alternatively, a single size suitable forinsertion into a wide range of different-sized bladders may be employed.Such a universal implant could be sized to the smallest bladder in therange. Another alternative is for the implant to be trimmed to size, atthe point of care, by the physician.

[0084] Implant 42 can be circular in cross-section, although other,preferably symmetrical, cross-sectional shapes could be employedespecially, for example, polygonal shapes such as hexagonal, octagonal,dodecagonal, or the like.

[0085] The wall thickness of implant 42 is preferably approximatelyuniform, although may be varied if desired. For example, skirt portion48 may have alternating thinner and thicker arcuately extending portionsto facilitate packing into the implantation device.

[0086] Optionally, implant 42 may include reinforcing structures such asribs 61 adhered to or molded into implant 42, which ribs 61 may beformed of a non-porous, structural biocompatible polymer, for example, apolyurethane. As shown in FIGS. 2 and 3, implant 42 optionally comprisesa pair of cross-like perpendicularly disposed semicircular ribs 61 oninner surface 52 of implant 42. Preferably, ribs 61 are sufficientlyflexible to bend to be accommodated in a delivery instrument and arelightly prestressed into the arcuate configuration shown in FIG. 2. Ribs61 can have a partial extent, for example, stopping short of the centerof the cross configuration. Such ribs can be employed in any desiredconfiguration to help the implants of the invention adopt a desiredconfiguration in situ. For example, in an alternative configuration,ribs 61 could comprise rings, or arcs extending around the interior, orexterior, of implant 42 approximately parallel with surface 60. However,ribs that can adopt a mostly straight line configuration in a compressedconfiguration of implant 42 are preferred.

[0087]FIG. 4 illustrates another embodiment where the thickness ofimplant 42 is varied in a useful manner. In the FIG. 4 embodiment, skirtportion 48 is provided with a number of peripheral ridges 58 to engagebladder inner walls 12. Ridges 58 extend preferably continuously aroundskirt portion 48 parallel to the lower periphery 60 of implant 42, in acircumferential manner in the case of a hemispherically shaped implant42. Alternatively, ridges 58 may be discontinuous with significant gapsbetween one ridge portion and the next. As shown, ridges 58 have anasymmetric sawtooth profile with an upper more gently sloped land 62 anda lower more steeply sloped land 64, referring to the orientation ofimplant 42 shown in FIG. 2, which corresponds approximately to theorientation preferred in an upright bladder 10. When employed with aresilient implant 42 having a diameter 44 slightly greater than therelevant cross-section of bladder 10, whereby implant 42 is urgedoutwardly into engagement with bladder inner walls 12, the asymmetry ofridges 58 gives them a cam-like action tending to urge implant 42upwardly in bladder 10, as bladder 10 repeatedly contracts duringurination. Furthermore, lower lands 64 tend to hold implant 42approximately in place, once it is suitably positioned, restraining itfrom encountering trigone 22.

[0088] While the illustrated embodiment of implant 42 is of continuous,monolithic, one-piece construction, it will be understood that otherconstructions may be employed. For example, implant 42 may be formedwith a number of uniformly distributed or localized relatively largepore openings. Rather than being of monolithic construction, implant 42may comprise multiple segments for example, from to 500, or from 10 to100, adhered or otherwise secured together, portions of disparatematerials interspersed together to form a coherent whole, or may be oflaminar construction with two or more layers adhered together ofmaterials of differing characteristics. Thus, implant 42 could comprisea relatively larger pored radially outer layer and a relatively smallerpored radially inner layer to deliver drug preferentially into the urineadjacent the bladder walls 12 rather than to the interior and lowerportions of the bladder where the drug will be voided during urination.Controlled, or limited retention of urine between implant 42 and thebladder inner walls 12, promoted by engagement of skirt portion 48 withbladder inner walls 12 can also help control drug losses attributable tourination.

[0089] The therapeutic agent delivery implant can also contain aradiopaque or sonically reflective substance for viewability of theimplant by radiography or ultrasound to determine the orientation,location and other features of the implant 42.

[0090] As is illustrated in FIG. 5, implant 42 may tend to reside in thedome of bladder 10. As bladder 10 expands due to filling and contractsdue to micturition, the implant 42 can be resiliently compressed andrelaxed, if necessary, by the bladder walls 12 so as to be retained inthe vicinity of bladder dome 38, clear of the sensitive trigone 22.

[0091] As is also illustrated in FIG. 5, device 46 can be a soliddomical shape with a lower surface as is illustrated by broken line 47.This configuration provides a more substantial implant device havingmore mass and, when constructed out of foam, substantial pore surfacearea that can support more of a biologically active substance than ashell-like configuration such as that shown in FIG. 5.

[0092] As illustrated in FIG. 6, a modified therapeutic agent deliveryimplant 70 additionally may optionally have a centrally attached cord 72or other pendant flexible, cord-like structure, which can be readilygripped, to facilitate removal of implant 70 from bladder 10, forexample by a forceps inserted through a cystoscope, or other suitableinstrument. Implant 70 is formed of a thin, flexible material so that itcan invert as it is drawn into the cystoscope or other introducerinstrument. If desired, cord 72 can be sufficiently long to extend fromimplant 42, into the urethra 30, or even long enough to extend throughthe urethra 30, and to project externally. Cord 72 is an example of thegripping member that may be attached to or part of any implant of anyshape or size according to the invention.

[0093] In one embodiment of the invention, implant 42 can include a loop56, tab or other grippable structure to facilitate retrieval of implant42 from a site of implantation. Loop 56 can, for example, comprise asingle piece of flexible material extending between opposed sides ofskirt portion 48 beneath upper portion 50. Alternatively, it could beY-shaped or cross-shaped, being secured to skirt portion 48 at three orfour spaced apart locations. Loop 56 is preferably formed of relativelyhigh tensile strength non-porous, polymeric material, although it couldbe formed of the same material as the body of implant 42. Loop 56 isintended to be gripped by a forceps inserted through an introducerinstrument.

[0094] Some additional possible embodiments of novel drug deliveryimplants pursuant to the invention are illustrated in FIGS. 7 to 13.Other embodiments will be, or will become, apparent to those skilled inthe art. These implants can with advantage all be constructed in onepiece from a resiliently compressible, spongy foam composite capable ofreleasably supporting useful quantities of a useful therapeutic agent onits pore surfaces, or may be constructed from other suitable materials,as described herein.

[0095] As shown in FIG. 7, an implant 80 has an approximately sphericalshape and is sized to be readily accommodated within the bladder, beingfor example, from about 1 to about 10 cm in diameter, preferably fromabout 2 to about 6 cm in diameter. A particularly preferred diameter isa maximal size providing a sphere which can just be accommodated withinthe minimum normal bladder volume, without significant compression ofthe implant 80.

[0096] Implant 80 is solid in the sense that the whole volume of theimplant is filled by foam or other suitable implant material, incontrast to the relatively thin-wall, shell-like construction of implant42 which has a hemispherical outer periphery and a hemispherical hollowinterior. However, this solid material volume of implant 80 includes amyriad of small internal interconnected hollow pore spaces, which areaccessible by external fluids, such as body fluids in situ, to providean extended surface area which with a suitable surface coating can beemployed for drug release.

[0097] The implant 90 illustrated in FIG. 8 has a fusiform orellipsoidal shape, much like a football having rounded ends 92 andcross-sections perpendicular to the paper, along the length between ends92, which are approximately, or generally, circular. The maximum lengthof implant 90 between ends 92, that can be readily accommodated in agiven bladder 10, may be a little greater than the equivalent maximalsphere 80 for the same bladder 10 and the maximum cross-sectionaldiameter may be a little less. As shown in FIG. 9, fusiform implant 90can float relatively freely within bladder 10 with no particularorientation being required.

[0098] An implant 94 in FIG. 10 has a bullet-like shape, and an implant96 in FIG. 11 has a cylindrical shape. Other suitable solid implantconfigurations (not shown) include cubic, elongated cuboid, trapezoidal,parallelepiped, ellipsoid, fusiform, rod, tube, sleeve, elongatedprismatic form, or a folded, coiled, helical or, other more compactconfiguration irregular, and other solid shapes having more or less flatsurfaces. Some elongation of the shape is advantageous for compressionfor implantation. In another embodiment, the elastomeric matrix or thescaffold having such a form has a diameter or other maximum dimensionfrom about 2 cm to about 10 cm.

[0099] The longer and thinner shape of implant 90, 94, or 96 as comparedwith, for example, a sphere, renders implant 90, 94, or 96 particularlysuitable to be laterally compressed to fit into an introducerinstrument. As shown in FIG. 20 below, an implant such as implant 42,90, 94, or 96 can readily be compressed into the small pencil-likeobject and fitted into the cylindrical end portion of an introducercatheter or the like, where a plunger enables the compressed implant tobe discharged from the catheter or the like at the desired site ofimplantation, for example, bladder 10.

[0100] Implants 80, 90, 94, 96 and the other solid implants describedare useful, space-occupying, free-floating, preferably buoyant, implantswhich have the following advantages:

[0101] ease of fabrication of relatively simple shapes;

[0102] ease of loading into an introducer cannula, trocar, catheter, orany type of minimally invasive rigid or flexible instrument, optionallyone incorporating visualization or electromechanics, such as acystoscope, laproscope, arthroscope, or endoscope, or the like;

[0103] a large therapeutic agent-bearing volume of implant for a givenbladder size; and

[0104] ease of retrievability because an end or any other portion of theimplant 80, 90, 94, or 96 can be gripped by a cannula-inserted forcepsenabling the implant to be withdrawn into the cannula, and be compressedto fit the cannula as the forceps is retracted.

[0105] A large implant volume of appropriate porosity provides a largeinternal surface area for contacting drug-bearing materials with urine.Use of a highly porous implant material having a low bulk densityassures that the urine capacity of bladder 10 is not unacceptablyimpacted because a major proportion of the volume of the implant can beoccupied by urine, as will be apparent from the physical properties ofthe implant material. Consistent with what is shown in FIG. 9, suchsolid implants can float relatively freely within bladder 10 with noparticular orientation being required.

[0106] The implants shown in at least FIGS. 7 to 11 have relatively highvolume to external surface area ratios. Such ratios make such implantswell-suited to relatively long term delivery of therapeutic agents orother active ingredients at relatively low to moderate dosage rates.

[0107] Solid shape implants, for example, those of FIGS. 7 to 11, arerelatively unlikely to contact the trigone or block the ureter openings25, 27. However, even should the implants locate themselves in such aposition, use of a porous implant material will ensure that urine flowis not blocked. Use of a flexible, resilient implant material canameliorate the response of trigone 22 to contact. If desired, arelatively soft implant material may be employed, or the outer surfaceof any of the novel implants described herein can be coated with a softmaterial for example, a hydrophilic polyurethane layer which may beadditional to any internal pore coating layer. Any such protective layershould be applied so as to permit liberal fluid access to the interiorof the implant, for example, by applying such a layer only to the moreprominent surfaces of the implant 42, 80, 90, 94, or 96 that mayencounter trigone 22, for example, to the ends 92 of implant 90 or tothe lower peripheral surface 60 of implant 42.

[0108] Other suitable solid shapes providing some or all of theabove-described advantages will be or become apparent to those skilledin the art.

[0109] The embodiment of implant 100 shown in FIGS. 12 and 13 has theshape of a biconcave disc, much like a contraceptive diaphragm or redblood cell. Implant 100 comprises a relatively thin central disc 102 anda thickened circumferential rim 104. Rim 104 provides storage volume forbiological actives adjacent inner walls 12 of bladder 10 or otherbiological structure. The thinner disk portion 102 facilitatescompression in to a shape that will fit within an introducer instrument.Implant 100 can optionally be buoyant and be free floating withinbladder 10, and sized to be a relatively close fit into the dome ofbladder 10. When suitably sized to a particular bladder 10 and placed inthe dome of the bladder, the biconcave shape may be retained in place asbladder 10 contracts on device 100.

[0110] The spaghetti strand implant 110 shown in FIG. 14 has aconfiguration resembling a piece of cooked spaghetti, linguini or othersuch pasta and comprises a single long flexible piece of foam or othersuitable porous or extended surface area material, as described herein.Spaghetti strand implant 110 may have any desired cross-sectional shapesuch as square, circular or flattened to give the implant a ribbon-likeconfiguration. Alternatively, implant 110 may be tubular, having anannular cross-sectional shape. Though shown as ended, spaghetti strandimplant 110 may comprise an endless loop. While a uniform cross-sectionthroughout the length of implant 110 is convenient, it is not necessary.

[0111] Spaghetti strand implant 110 can have any suitable dimensions,for example, a length of from about 0.5 to about 50 cm, preferably fromabout 2 to about 25 cm, more preferably from about 5 to about 10 cm.Spaghetti strand implant 110 can have any suitable averagecross-sectional area, for example from about 0.0025 cm² to about 1 cm²,preferably from about 0.01 cm² to about 0.25 cm². The length can be fromabout 2 times to about 100 times the average width of the strand,preferably from about 5 times to about 20 times the average width.

[0112] Spaghetti strand implant 110 may be folded and compressed to fitinto an introducer instrument and is easily withdrawn by gripping with aforceps, preferably in a central region of the implant 110. Spaghettistrand implant 110 has modest mass can be fabricated to have a densityclose to that of urine, or a little less for buoyancy and willaccordingly have little irritant effect if it should contact the urine.

[0113] Spaghetti strand implant 110 has the advantages of easy insertionand removal via a cannula or other removal instrument and of having alarge external surface area relatively to its volume.

[0114] The implant 120 shown in FIG. 15 can be described as a mopheadimplant and has a head portion 122 from which project strands 124 offoam or other suitable material. Strands 124 may be similar to spaghettistrand 110 illustrated in FIG. 9. The configuration of mophead implant120 provides a very large external surface area for contact with theurine. As with implant 90 shown in FIG. 9, mophead implant 120 can floatrelatively freely within bladder 10 with no particular orientation beingrequired.

[0115] Mophead implant 120 also has the advantages of easy insertion andremoval via a cannula and of having a large external surface arearelatively to its volume. Depending upon the particular characteristicsof the release mechanisms employed spaghetti strand implant 110 andmophead implant 120 are both suitable for delivering high dosages ofdrugs over relatively short intervals.

[0116] Another embodiment of implant (not shown) comprises multiplespaghetti strand pieces of implant material assembled, or intertwinedtogether into a ball from which the strand ends may project, analogouslyto a ball of spaghetti. The strands may be woven, tied. stitched,adhered or otherwise secured together. As an alternative to foam, thestrands may be constituted by a woven or nonwoven porous fabric or othersuch material to which a desired biologic agent is secured, as describedherein.

[0117] If desired, multiple suitably sized implants can reside inbladder 10, or another implantation site, simultaneously. Differentimplants bearing different therapeutic agents or therapeutic agentformulations designed to serve separate, non-interfering ends or to workco-operatively may be simultaneously resident in the site ofimplantation. Spaghetti strand implant 110 is particularly well suitedto this purpose.

[0118] Expansion in situ, especially in the bladder after delivery in acompressed state through the urethra, can be effected by the inherentrecoverable nature of the material of the implants, arising out ofresilient structural components of the implants. Alternatively, asuitable expansion mechanism, for example, an umbrella-like lever andspoke mechanism, may be associated with or built into an implant, suchthat it is maniputable through a cannula, trocar, catheter, or any typeof minimally invasive rigid or flexible instrument, optionally oneincorporating visualization or electromechanics, such as a cystoscope,laproscope, arthroscope, or endoscope, or the like.

[0119] As stated above, the basic therapeutic agent delivery device ofthe invention comprises a reticulated, at least partially hydrophobicfoam scaffold with at least one therapeutic agent carried or absorbedthereon, preferably in a hydrophilic coating. Such coated foam scaffoldsare referred to as foam composites, and some of the benefits of theinventive implants and implant systems employing useful physicalcharacteristics of composite or coated or treated foams are as follows:

[0120] Agent Binding. A capacity to adsorb or covalently bond chemicalsor therapeutically active agents to the hydrophilic polyurethane layer.

[0121] Particle embedment. A capability to embed time-releasemicrospheres or other micropackages or particles within the hydrophiliclayer, which embedded entities are distributed in three-dimensionalspace held in place, relative to one another, and are supported, by thehydrophobic scaffold on which the hydrophilic layer is coated.

[0122] Controlled release. The binding and particle embedmentcapabilities can be utilized to provided an implant system for sustainedrelease of specific therapeutic agents in a controlled and definedfashion, that is, in a certain manner affecting either the location orthe timing of the release. Controlled release techniques have particularadvantages in the context of administering therapeutic agents. Forexample, the release rate of a therapeutic agent can be predicted anddesigned for an extended duration; this eliminates problems associatedwith patients neglecting to take required medication in specifieddosages at specified times. Many therapeutic agents have shorthalf-lives. Trapping these therapeutic agents in polymeric matricesincreases the time in which the therapeutic agent maintains itsactivity. Further, the site specific localization of a therapeutic agentachieved with a targeted delivery technique reduces or eliminatessystemic side effects that certain medications cause when administeredorally or intravenously in large doses.

[0123] Compressive elasticity. The compressive elasticity of a foamcomposite material useful according to the invention is valuable inenabling an implant to be loaded within a cannula, trocar, catheter, orany type of minimally invasive rigid or flexible instrument, optionallyone incorporating visualization or electromechanics, such as acystoscope, laproscope, arthroscope, or endoscope, or the like, forextended periods of time without compromising the ability of the foam toexpand to an uncompressed configuration, for example approximately toits original dimensions. Implant expansion from a compressed stateenables the implant to occupy space and allow urine or other body fluidflow to permeate the foam throughout the occupied space, enablingactives located anywhere in the foam to diffuse into the body fluid.Implant expansion from the compressed state, also may also enabledomical and other suitably shaped implants to fix themselves intoposition, in vivo, on a short-term or long-term basis.

[0124] Fluid Permeability. A preferred foam composite useful accordingto the invention is a reticulated polyurethane scaffold, which allowsfor substantial fluid flow-through, or permeability, permitting activedrugs and compounds to be carried away from within the implant in theambient fluid flow. Fluid permeability facilitates membrane transport oftherapeutically active substances from the scaffold, coating on thescaffold, or microspheres in the coating and delivery of thetherapeutically active substances externally of the implant, forexample, to the transitional mucous membrane of the bladder. Thecontinual filling and emptying of the bladder facilitates movement ofurine through the implant and leaching of actives.

[0125] Tensile Strength. The useful foam composite material can befabricated with excellent tensile strengthen allowing an implant to begrasped or retrieved with a hook or forceps and withdrawn into asuitable instrument such as a trocar or cannula for removal from theimplantation site, e.g., the bladder. Such grasping or hooking actioncould disrupt or tear less robust materials such as conventionalhydrophilic polyurethane. Implants constructed from useful foamcomposite materials employing a reticulated hydrophobic polyurethane asa substrate or scaffold material, provide an implant that can retain itsstructural integrity and be removed without undue difficulty.

[0126] Scaffold

[0127] The implant of this invention or the hydrophobic scaffold is aporous reticulated polymeric matrix formed of a biodurable polymer thatis resiliently-compressible so as to regain its shape after delivery toa biological site. The structure, morphology, and properties of theelastomeric matrices of this invention can be engineered or tailoredover a wide range of performance by varying the starting materialsand/or the processing conditions for different functional or therapeuticuses.

[0128] The porous biodurable elastomeric matrix is considered to bereticulated because its microstructure or the interior structurecomprises inter-connected open pores bounded by configuration of thestruts and intersections that constitute the solid structure. Thecontinuous interconnected void phase is the principle feature of areticulated structure.

[0129] Preferred scaffold materials for the implants have a porous andreticulated structure with sufficient and required liquid permeabilityand thus are selected to permit urine, or other appropriate bodilyfluids, to access interior drug-bearing surfaces of the implants duringthe intended period of implantation. This happens due to the presence ofinter-connected, reticulated open pores that form fluid passageways orfluid permeability providing fluid access all through and to theinterior of the matrix for elution of pharmaceutically-active agents,e.g., a drug, or other therapeutically useful materials. Such materialsmay optionally be secured to the interior surfaces of elastomeric matrixdirectly or through a coating. In one embodiment of the invention thecontrollable characteristics of the implants are selected to promote aconstant rate of therapeutic agent release during the intended period ofimplantation. Also, the passageways may be adjusted sufficiently topermit

[0130] Any of a variety of materials meeting the foregoing requirementsmay be employed. A preferred foam is a compressible, lightweightmaterial, chosen for its structural stability in situ, its ability tosupport the drug to be delivered, for high liquid permeability, and foran ability to substantially recover pre-compression shape and sizewithin the bladder to provide, when loaded with appropriate substances,a reservoir of therapeutic agents that can be released into the urine inthe bladder. Suitable materials are further described hereinbelow.

[0131] Preferred foams or the hydrophobic reticulated and porouspolymeric matrix materials for fabricating implants according to theinvention are flexible and resilient in recovery, so that the implantsare also compressible materials enabling the implants to be compressedand, once the compressive force is released, to then recover to, ortoward, substantially their original size and shape. For example, animplant can be compressed from a relaxed configuration or a size andshape to a compressed size and shape under ambient conditions, e.g., at25° C. to fit into the introducer instrument for insertion into thebladder or other suitable internal body site for in vivo delivery.Alternatively, an implant may be supplied to the medical practitionerperforming the implantation operation, in a compressed configuration,for example, contained in a package, preferably a sterile package. Theresiliency of the elastomeric matrix that is used to fabricate theimplant causes it to recover to a working size and configuration insitu, at the implantation site, after being released from its compressedstate within the introducer instrument. The working size and shape orconfiguration can be substantially similar to its original size andshape after the in situ recovery.

[0132] Preferred scaffolds are reticulated, interconnected porespolymeric materials, having sufficient structural integrity anddurability to endure the intended biological environment, for theintended period of implantation. For structure and durability, at leastpartially hydrophobic polymeric scaffold materials are preferredalthough other materials may be employed if they meet the requirementsdescribed herein. Materials are preferably elastomeric in that they canbe compressed easily and resiliently recover to substantially thepre-compression state. Alternative porous polymeric materials thatpermit biological fluids to have ready access throughout the interior ofan implant may be employed, for example, woven or nonwoven fabrics ornetworked composites of microstructural elements of various forms.

[0133] The partially hydrophobic scaffold is preferably constructed of amaterial selected to be sufficiently biodurable, for the intended periodof implantation that the implant will not to lose its structuralintegrity during the implantation time in a biological environment. Thebiodurable elastomeric matrices forming the scaffold do not exhibitsignificant symptoms of breakdown, degradation, erosion or significantdeterioration of mechanical properties relevant to their use whenexposed to biological environments and/or bodily stresses for periods oftime commensurate with the use of the implantable device such ascontrolled release or elution of therapeutic agents and/orpharmaceutically-active agents, e.g., a drug, or other biologicallyuseful materials over a period of time. In one embodiment, the desiredperiod of exposure is to be understood to be at least 29 days. Thismeasure is intended to avoid scaffold materials that may decompose ordegrade into fragments for example, fragments that could move into theneck of the bladder, and possibly block the urethra or cause similarblockages elsewhere in a patient's body or cause unwanted tissueresponse.

[0134] The void phase, preferably continuous and interconnected, of thea porous reticulated polymeric matrix that is used to fabricate theimplant of this invention may comprise as little as 50% by volume of theelastomeric matrix, as compared to the volume provided by theinterstitial spaces of elastomeric matrix before any optional interiorpore surface coating or layering is applied. In one embodiment, thevolume of the void phase as just defined, is from about 70% to about 99%of the volume of the elastomeric matrix. In another embodiment, thevolume of the void phase is from about 80% to about 98% of the volume ofelastomeric matrix. In another embodiment, the volume of the void phaseis from about 90% to about 98% of the volume of elastomeric matrix.

[0135] As used herein, when a pore is spherical or substantiallyspherical, its largest transverse dimension is equivalent to thediameter of the pore. When a pore is non-spherical, for example,ellipsoidal or tetrahedral, its largest transverse dimension isequivalent to the greatest distance within the pore from one poresurface to another, e.g., the major axis length for an ellipsoidal poreor the length of the longest side for a tetrahedral pore. For thoseskilled in the art, one can routinely estimate the pore frequency fromthe average cell diameter in microns.

[0136] In one embodiment of the invention, the porous reticulatedpolymeric matrix that is used to fabricate the implant of this inventionto provide adequate fluid permeability, the average diameter or otherlargest transverse dimension of pores is from about 50 μm to about 2000μm (i.e., from about 300 to about 10 pores per linear inch), preferablyfrom about 50 μm to about 800 μm (i.e., from about 300 to about 25 poresper linear inch), more preferably from about 100 μm to about 500 μm(i.e, from about 150 to about 35 pores per linear inch), and mostpreferably between about 200 μm and about 400 μm (i.e., between about 80and 40 pores per linear inch.).

[0137] In another embodiment of the invention, elastomeric matrices thatare used to fabricate the scaffold part of this invention havesufficient resilience to allow substantial recovery, e.g., to at leastabout 50% of the size of the relaxed configuration in at least onedimension, after being compressed for implantation in the human body,for example, a low compression set, e.g., at 25° C. or 37° C., andsufficient strength and flow-through for the matrix to be used forcontrolled release of therapeutic and/or pharmaceutically-active agents,such as a drug, and for other medical applications. In anotherembodiment, elastomeric matrices of the invention have sufficientresilience to allow recovery to at least about 60% of the size of therelaxed configuration in at least one dimension after being compressedfor implantation in the human body. In another embodiment of theinvention, elastomeric matrices of the invention have sufficientresilience to allow recovery to at least about 90% of the size of therelaxed configuration in at least one dimension after being compressedfor implantation in the human body.

[0138] In another embodiment of the invention, the porous reticulatedpolymeric matrix that is used to fabricate the implants of thisinvention has any suitable bulk density, also known as specific gravity,consistent with its other properties. For example, in one embodiment ofthe invention, the bulk density may be from about 0.005 to about 0.15g/cc (from about 0.31 to about 9.4 lb/ft³), preferably from about 0.015to about 0.115 g/cc (from about 0.93 to about 7.2 lb/ft³) and mostpreferably from about 0.024 to about 0.104 g/cc (from about 1.5 to about6.5 lb/ft³).

[0139] The reticulated elastomeric matrix has sufficient tensilestrength such that it can withstand normal manual or mechanical handlingduring its intended application and during post-processing steps thatmay be required or desired without tearing, breaking, crumbling,fragmenting, or otherwise disintegrating, shedding pieces or particles,or otherwise losing its structural integrity. The tensile strength ofthe starting material(s) should not be so high as to interfere with thefabrication or other processing of elastomeric matrix. Thus, forexample, in one embodiment of the invention, the porous reticulatedpolymeric matrix that is used to fabricate the implants of thisinvention may have a tensile strength of from about 700 to about 52,500kg/m² (from about 1 to about 75 psi). In another embodiment of theinvention, elastomeric matrix may have a tensile strength of from about700 to about 21,000 kg/m² (from about 1 to about 30 psi). Sufficientultimate tensile elongation is also desirable. For example, in anotherembodiment of the invention, a reticulated elastomeric matrix has anultimate tensile elongation of at least about 100% to at least about500%.

[0140] In one embodiment of the invention, reticulated elastomericmatrix that is used to fabricate the implants of this invention has acompressive strength of from about 700 to about 140,000 kg/m² (fromabout 1 to about 200 psi) at 50% compression strain. In anotherembodiment, reticulated elastomeric matrix has a compressive strength offrom about 7,000 to about 210,000 kg/m² (from about 10 to about 300 psi)at 75% compression strain.

[0141] In another embodiment of the invention, reticulated elastomericmatrix that is used to fabricate the implants of this invention has acompression set, when compressed to 50% of its thickness at about 25°C., of not more than about 30%. In another embodiment of the invention,elastomeric matrix has a compression set of not more than about 20%. Inanother embodiment of the invention, elastomeric matrix has acompression set of not more than, about 10%. In another embodiment ofthe invention, the elastomeric matrix has a compression set of not morethan about 5%.

[0142] In another embodiment of the invention, the reticulatedelastomeric matrix that is used to fabricate the implants of thisinvention has a tear strength of from about 0.18 to about 1.78 kg/linearcm (from about 1 to about 10 lbs/linear inch).

[0143] In a preferred embodiment of a composite foam for use in thepractice of the present invention, the foam composite comprises apolyether polyol or polyether polysiloxane based hydrophilicpolyurethane coated on the pore surfaces of a hydrophobic polyurethanefoam scaffold. Preferred composite foams can have a density of fromabout 0.03 g/cc to about 0.10 g/cc and a weight ratio of open cellhydrophilic polyurethane coating to the weight of the hydrophobic foamis from about 0.01 to about 15, and preferably from about 0.5 to about10.

[0144] In another embodiment of the invention the reticulatedelastomeric matrix that is used to fabricate the implant can be readilypermeable to liquids, permitting flow of liquids, including urine,through the composite device of the invention. The water permeability ofthe reticulated elastomeric matrix is from about 25 l/min./psi/cm² toabout 1000 l/min./psi/cm², preferably from about 100 l/min./psi/cm² toabout 600 l/min./psi/cm².

[0145] The implant of the invention device allows for the control of theflow rate of liquid through device by adjustment of severalcharacteristics. Firstly, the pore-size of pores of carrier, rathersupport may be adjusted. For example, in the case of the preferredcomposite foam, the open-pore structure can be produced in a range ofprecisely controlled pore sizes that contain void volumes of up to 98%.Various pore sizes, typically from about 35 to about 150 pores perlinear inch (ppi), enable the use of the hydrophobic polyurethane inspecific applications. The high porosity of material helps controlpermeability and adds to design flexibility.

[0146] In general, a suitable, porous, biodurable, reticulated,elastomeric, partially hydrophobic polymeric matrix that is used tofabricate an implant of the invention or for use as scaffold materialfor the implant in the practice of the present invention, in oneembodiment sufficiently well characterized, comprises one of theelastomers that have or can be formulated with the desirable mechanicalproperties described in the present specification and have a chemistryfavorable to biodurability such that they provide a reasonableexpectation of adequate biodurability.

[0147] Various reticulated hydrophobic polyurethane foams are suitablefor this purpose. In one embodiment, structural materials for theinventive porous elastomers are synthetic polymers, especially, but notexclusively, elastomeric polymers that are resistant to biologicaldegradation, for example, polycarbonate polyurethanes, polyetherpolyurethanes, polysiloxanes, and the like. Such elastomers aregenerally hydrophobic but, pursuant to the invention, may be treated tohave surfaces that are less hydrophobic or somewhat hydrophilic. Inanother embodiment of the invention, such elastomers may be producedwith surfaces that are less hydrophobic or somewhat hydrophilic.

[0148] The invention provides a porous biodurable reticulatableelastomeric partially hydrophobic polymeric scaffold material forfabricating an implant or a material. More particularly, in oneembodiment, the invention provides a biodurable elastomeric polyurethanematrix which comprises a polycarbonate polyol component and anisocyanate component by polymerization, crosslinking and foaming,thereby forming pores, followed by reticulation of the foam to provide abiodurable reticulatable elastomeric product. The product is designatedas a polycarbonate polyurethane, being a polymer comprising urethanegroups formed from, e.g., the hydroxyl groups of the polycarbonatepolyol component and the isocyanate groups of the isocyanate component.In this embodiment, the process employs controlled chemistry to providea reticulated elastomer product with good biodurability characteristics.The foam product employing chemistry that avoids biologicallyundesirable or nocuous constituents therein.

[0149] In one embodiment of the invention, the starting material of theporous biodurable reticulated elastomeric partially hydrophobicpolymeric matrix contains at least one polyol component. For thepurposes of this application, the term “polyol component” includesmolecules comprising, on the average, about 2 hydroxyl groups permolecule, i.e., a difunctional polyol or a diol, as well as thosemolecules comprising, on the average, greater than about 2 hydroxylgroups per molecule, i.e., a polyol or a multi-functional polyol.Exemplary polyols can comprise, on the average, from about 2 to about 5hydroxyl groups per molecule. In one embodiment, as one startingmaterial, the process employs a difunctional polyol component. In thisembodiment, because the hydroxyl group functionality of the diol isabout 2. In another embodiment, the soft segment is composed of a polyolcomponent that is generally of a relatively low molecular weight,typically from about 1,000 to about 6,000 Daltons. Thus, these polyolsare generally liquids or low-melting-point solids. This soft segmentpolyol is terminated with hydroxyl groups, either primary or secondary.

[0150] Examples of suitable polyol components are polyether polyol,polyester polyol, polycarbonate polyol, hydrocarbon polyol, polysiloxanepolyol, poly(ether-co-ester) polyol, poly(ether-co-carbonate) polyol,poly(ether-co-hydrocarbon) polyol, poly(ether-co-siloxane) polyol,poly(ester-co-carbonate) polyol, poly(ester-co-hydrocarbon) polyol,poly(ester-co-siloxane) polyol, poly(carbonate-co-hydrocarbon) polyol,poly(carbonate-co-siloxane) polyol, poly(hydrocarbon-co-siloxane)polyol, or mixtures of two or more thereof.

[0151] Useful polysiloxane polyols include oligomers of, e.g., alkyland/or aryl substituted siloxanes such as dimethyl siloxane, diphenylsiloxane or methyl phenyl siloxane, comprising hydroxyl end-groups.Polysiloxane polyols with an average number of hydroxyl groups permolecule greater than 2, e.g., a polysiloxane triol, can be made byusing, for example, methyl hydroxymethyl siloxane, in the preparation ofthe polysiloxane polyol component.

[0152] A particular type of polyol need not, of course, be limited tothose formed from a single monomeric unit. For example, a polyether-typepolyol can be formed from a mixture of ethylene oxide and propyleneoxide. Additionally, in another embodiment, copolymers or copolyols canbe formed from any of the above polyols by methods known to those in theart. Thus, the following binary component polyol copolymers can be used:poly(ether-co-ester) polyol, poly(ether-co-carbonate) polyol,poly(ether-co-hydrocarbon) polyol, poly(ether-co-siloxane) polyol,poly(ester-co-carbonate) polyol, poly(ester-co-hydrocarbon) polyol,poly(ester-co-siloxane) polyol, poly(carbonate-co-hydrocarbon) polyol,poly(carbonate-co-siloxane) polyol and poly(hydrocarbon-co-siloxane)polyol. For example, a poly(ether-co-ester) polyol can be formed fromunits of polyethers formed from ethylene oxide copolymerized with unitsof polyester comprising ethylene glycol adipate. In another embodiment,the copolymer is a poly(ether-co-carbonate) polyol,poly(ether-co-hydrocarbon) polyol, poly(ether-co-siloxane) polyol,poly(carbonate-co-hydrocarbon) polyol, poly(carbonate-co-siloxane)polyol, poly(hydrocarbon-co-siloxane) polyol or mixtures thereof. Inanother embodiment, the copolymer is a poly(carbonate-co-hydrocarbon)polyol, poly(carbonate-co-siloxane) polyol,poly(hydrocarbon-co-siloxane) polyol or mixtures thereof. In anotherembodiment, the copolymer is a poly(carbonate-co-hydrocarbon) polyol.For example, a poly(carbonate-co-hydrocarbon) polyol can be formed bypolymerizing 1,6-hexanediol, 1,4-butanediol and a hydrocarbon-typepolyol with carbonate.

[0153] Furthermore, in another embodiment of the invention, mixtures,admixtures and/or blends of polyols and copolyols can be used in theelastomeric matrix of the present invention. In another embodiment, themolecular weight of the polyol is varied. In another embodiment, thefunctionality of the polyol is varied.

[0154] In another embodiment of the invention, the starting material ofthe porous biodurable reticulated elastomeric partially hydrophobicpolymeric matrix contains at least one isocyanate component and,optionally, at least one chain extender component to provide theso-called “hard segment”. For the purposes of this application, the term“isocyanate component” includes molecules comprising, on the average,about 2 isocyanate groups per molecule as well as those moleculescomprising, on the average, greater than about 2 isocyanate groups permolecule. The isocyanate groups of the isocyanate component are reactivewith reactive hydrogen groups of the other ingredients, e.g., withhydrogen bonded to oxygen in hydroxyl groups and with hydrogen bonded tonitrogen in amine groups of the polyol component, chain extender,crosslinker and/or water.

[0155] In another embodiment of the invention, the average number ofisocyanate groups per molecule in the isocyanate component is about 2.In another embodiment of the invention, the average number of isocyanategroups per molecule in the isocyanate component is greater than about 2is greater than 2.

[0156] The isocyanate index, a quantity well known to those in the art,is the mole ratio of the number of isocyanate groups in a formulationavailable for reaction to the number of groups in the formulation thatare able to react with those isocyanate groups, e.g., the reactivegroups of diol(s), polyol component(s), chain extender(s) and water,when present. In one embodiment of the invention, the isocyanate indexis from about 0.9 to about 1.1. In another embodiment of the invention,the isocyanate index is from about 0.9 to about 1.02. In anotherembodiment, the isocyanate index is from about 0.98 to about 1.02. Inanother embodiment of the invention, the isocyanate index is from about0.9 to about 1.0. In another embodiment of the invention, the isocyanateindex is from about 0.9 to about 0.98.

[0157] The elastomeric polyurethane may contain from about 20 to 70% byweight of hard segment, preferably from about 25 to 35% by weight ofhard segment and may contain from about 30 to 85% by weight of softsegment, preferably from about 50 to 80% by weight of soft segment,based upon the total weight of the polyurethane.

[0158] Exemplary diisocyanates include aliphatic diisocyanates,isocyanates comprising aromatic groups, the so-called “aromaticdiisocyanates”, and mixtures thereof. Useful aliphatic diisocyanatesinclude tetramethylene diisocyanate, cyclohexane-1,2-diisocyanate,cyclohexane-1,4-diisocyanate, hexamethylene diisocyanate, isophoronediisocyanate, methylene-bis-(p-cyclohexyl isocyanate) (“H₁₂ MDI”), andmixtures thereof. Useful aromatic diisocyanates include p-phenylenediisocyanate, 4,4′-diphenylmethane diisocyanate (“4,4′-MDI”),2,4′-diphenylmethane diisocyanate (“2,4′-MDI”), 2,4-toluene diisocyanate(“2,4-TDI”), 2,6-toluene diisocyanate(“2,6-TDI”), m-tetramethylxylenediisocyanate, and mixtures thereof.

[0159] In one embodiment of the invention, the isocyanate componentcontains a mixture of at least from about 5% to 50% by weight of2,4′-MDI and with from about 50 to 95% by weight of 4,4′-MDI, based uponthe total weight of the component. Without being bound by any particulartheory, it is thought that the use of higher amounts of 2,4′-MDI in ablend with 4,4′-MDI results in a softer elastomeric matrix because ofthe disruption of the crystallinity of the hard segment arising out ofthe asymmetric 2,4′-MDI structure.

[0160] In another embodiment of the invention, the starting material ofthe porous biodurable reticulated elastomeric partially hydrophobicpolymeric matrix contains suitable chain extenders, preferably for thehard segments, including, but not limited to, diols, diamines, alkanolamines and mixtures thereof In another embodiment of the invention, thechain extender is an aliphatic diol having from 2 to 10 carbon atoms. Inanother embodiment of the invention, the diol chain extender is selectedfrom the group consisting of ethylene glycol, 1,2-propane diol,1,3-propane diol, 1,4-butane diol, 1,5-pentane diol, diethylene glycol,triethylene glycol, and mixtures thereof. In another embodiment of theinvention, the chain extender is a diamine having from 2 to 10 carbonatoms. In another embodiment of the invention, the diamine chainextender is selected from the group consisting of ethylene diamine,1,3-diaminobutane, 1,4-diaminobutane, 1,5 diaminopentane,1,6-diaminohexane, 1,7-diaminoheptane, 1,8-diaminooctane, isophoronediamine and mixtures thereof. In another embodiment of the invention,the chain extender is an alkanol amine having from 2 to 10 carbon atoms.In another embodiment of the invention, the alkanol amine chain extenderis selected from the group consisting of diethanolamine,triethanolamine, isopropanolamine, dimethylethanolamine,methyldiethanolamine, diethylethanolamine, and mixtures thereof.

[0161] In one embodiment of the invention, the starting material of theporous biodurable reticulated elastomeric partially hydrophobicpolymeric matrix contains a small quantity of an optional ingredient,such as a multi-functional hydroxyl compound or other crosslinker havinga functionality greater than 2, e.g., glycerol, is present to facilitatecrosslinking. In another embodiment of the invention, the optionalmulti-functional crosslinker is present in an amount just sufficient toachieve a stable foam, i.e., a foam that does not collapse to becomenon-foamlike. Alternatively, or in addition, polyfunctional adducts ofaliphatic and cycloaliphatic isocyanates can be used to impartcrosslinking in combination with aromatic diisocyanates. Alternatively,or in addition, polyfunctional adducts of aliphatic and cycloaliphaticisocyanates can be used to impart crosslinking in combination withaliphatic diisocyanates.

[0162] In one embodiment of the invention, the starting material of theporous biodurable reticulated elastomeric partially hydrophobicpolymeric matrix is a commercial polyurethane polymer. Polyurethanepolymers are linear, not crosslinked, polymers, and therefore they aresoluble, can be melted, readily analyzable, and readily characterizable.In this embodiment of the invention, the staring polymer provides goodbiodurability characteristics. The reticulated elastomeric matrix isproduced by taking a solution of the commercial polymer such aspolyurethane and charging it into a mold that has been fabricated withsurfaces defining a microstructural configuration for the final implantor scaffold, solidifying the polymeric material and removing thesacrificial mold by melting, dissolving or subliming-away thesacrificial mold. The foam product employing a foaming process thatavoids biologically undesirable or nocuous constituents therein.

[0163] Of particular interest are thermoplastic elastomers such aspolyurethanes whose chemistry is associated with good biodurabilityproperties, for example. In one embodiment of the invention, suchthermoplastic polyurethane elastomers include polycarbonatepolyurethanes, polyester polyurethanes, polyether polyurethanes,polysiloxane polyurethanes, polyurethanes with so-called “mixed” softsegments, and mixtures thereof. Mixed soft segment polyurethanes areknown to those skilled in the art and include, e.g.,polycarbonate-polyester polyurethanes, polycarbonate-polyetherpolyurethanes, polycarbonate-polysiloxane polyurethanes,polyester-polyether polyurethanes, polyester-polysiloxane polyurethanesand polyether-polysiloxane polyurethanes. In another embodiment of theinvention, the thermoplastic polyurethane elastomer comprises at leastone diisocyanate in the isocyanate component, at least one chainextender and at least one diol, and may be formed from any combinationof the diisocyanates, difunctional chain extenders and diols describedin detail above.

[0164] In one embodiment of the invention, the weight average molecularweight of the thermoplastic elastomer is from about 30,000 to about500,000 Daltons. In another embodiment of the invention, the weightaverage molecular weight of the thermoplastic elastomer is from about50,000 to about 250,000 Daltons.

[0165] Some suitable thermoplastic polyurethanes for practicing theinvention, in one embodiment suitably characterized as described herein,include, but are not limited to, polyurethanes with mixed soft segmentscomprising polysiloxane together with a polyether and/or a polycarbonatecomponent, as disclosed by Meijs et al. in U.S. Pat. No. 6,313,254; andthose polyurethanes disclosed by DiDomenico et al. in U.S. Pat. Nos.6,149,678, 6,111,052 and 5,986,034, all of which are incorporated hereinby reference.

[0166] Some commercially-available thermoplastic elastomers suitable foruse in practicing the present invention include the line ofpolycarbonate polyurethanes supplied under the trademark BIONATE® by ThePolymer Technology Group Inc. (Berkeley, Calif.). For example, the verywell-characterized grades of polycarbonate polyurethane polymer BIONATE®80A, 55 and 90 are soluble in THF, processable, reportedly have goodmechanical properties, lack cytotoxicity, lack mutagenicity, lackcarcinogenicity and are non-hemolytic. Another commercially-availableelastomer suitable for use in practicing the present invention is theCHRONOFLEX® C line of biodurable medical grade polycarbonate aromaticpolyurethane thermoplastic elastomers available from CardioTechInternational, Inc. (Woburn, Mass.). Yet another commercially-availableelastomer suitable for use in practicing the present invention is thePELLETHANE® line of thermoplastic polyurethane elastomers, in particularthe 2363 series products and more particularly those products designated81A and 85A, supplied by The Dow Chemical Company (Midland, Mich.).These commercial polyurethane polymers are linear, not crosslinked,polymers, therefore, they are soluble, readily analyzable and readilycharacterizable.

[0167] Coatings and Delayed Drug Delivery

[0168] A foam composite according to the invention can comprise ascaffold of reticulated, open cell hydrophobic and preferably biostablematerial having a plurality of surfaces defining a plurality of pores,and a coating of a substantially hydrophilic foam material disposed uponthe surfaces of the hydrophobic foam and within pores. In anotherembodiment, a foam composite according to the invention can comprise ascaffold of reticulated, open cell hydrophobic material having aplurality of surfaces defining a plurality of pores, and a coating of asubstantially hydrophilic material layer in the form or a film orcoating disposed upon the surfaces of the hydrophobic foam and withinpores. The hydrophilic foam or the hydrophilic material film or coatingcan be polymeric in nature. The polymer forming the film or the coatingcan be both non-biodegradable and degradable. The reticulated nature ofthe scaffold is advantageous due to the characteristic large surfacearea, which is suitable for carrying a coating and/or large quantitiesof therapeutic agents. The cells or pores in the hydrophobic foams mayvary in their degree of openness or interconnection (reticulation)depending upon the application. Open cell hydrophobic foams may have areticulated, substantially reticulated, or a non-reticulated structure.Hydrophobic foams having a more open, reticulated structure lendthemselves to applications in which a gas or liquid is passed throughthe structure, as in a filter, and where fluid flow and pressure dropconsiderations are of particular importance. Such foam compositeexhibits structural characteristics of the hydrophobic foam andabsorbency characteristics of the hydrophilic foam or a hydrophiliclayer. Those skilled in the art will understand how to vary the degreeof openness as well as the pore size of pores.

[0169] To facilitate immobilization of the drug on the scaffold, thescaffold may be hydrophilized or coated with a hydrophilic coating tofacilitate attachment of therapeutic agent or therapeutic agent drugbearing structures such as biologically erodible microspheres,microcapsules or other micropackages. Hydrophilization may comprisetreatment of the hydrophobic material to render the surfaces partiallyhydrophilic or application of an adhesive or application of ahydrophilic coating, or deposit of a hydrophilic foam, for example, asdescribed in Thomson, U.S. Pat. No. 6,617,014, incorporated herein byreference. In another embodiment, hydrophilization may comprise acombination of treatment of the hydrophobic material to render thesurfaces partially hydrophilic, application of an adhesive, applicationof a hydrophilic coating, and deposit of a hydrophilic foam.

[0170] The hydrophilic foam coating can be made from polyuretanescontaining appropriate and suitable isocyanate and polyols. Isocyanatessuitable for this invention are aromatic, such as, for example, toluenedilsocyanate (TDI) or methylene diphenyl isocyanate (MDI), or with aaliphatic duisosyanate, such as hydrogenated MDI or isopheronedilsocyanate. One example of polyol is polyether polyols which arehomopolymers of ethylene oxide, also known as polyethylene glycols, orcopolymers of ethylene oxide and propylene oxides. Other examples ofsuitable polyols are polyester polyol, poly(ether-co-ester) polyol,poly(ether-co-hydrocarbon) polyol, poly(ether-co-siloxane) polyol,poly(ester-co-siloxane) polyol,poly(ether-co-carbonate) polyol,poly(ester-co-carbonate) polyol, poly(ester-co-hydrocarbon) polyol, ormixtures thereof.

[0171] Hydrophilic polyurethanes foams are preferably made by theso-called pre-polymer or pseudo pre-polymer method. In this technique,the polyol and the isocyanate are reacted in various ratios and byvarious reaction schemes to produce an intermediate product called apre-polymer or quasi pre-polymer. This is then emulsified in an aqueousphase to produce the final foam coating. In another embodiment of theinvention, the hydrophilic foam coating is prepared by contacting with asolution of a prepolymer in a solvents, such as DMF,or DMAC or NMP, bycoating, spraying or dipping and contacting, and then the coated orotherwise prepolymer impregnated reticulated hydrophobic polyurethane issqueezed or spread or dispersed and optionally hung in place to removethe excess prepolymer solution followed by air drying or placing undervacuum to remove the solvent and finally curing in contact with water.The curing can be accomplished a water bath or in a humidity chamber orany space with sufficient environmental humidity.

[0172] Prepolymers suitable for use in the present invention areisocyanate-capped polyether prepolymers with an NCO functionality ofgreater than 5% as more particularly described below. The prepolymersare preferably based on polyether polyols capped with aromaticisocyanates such as for example toluene diisocyanate (TDI) or methylenediphenyl isocyanate (MDI) or with aliphatic isocyanates, such as, forexample isopherone diisocyanate (IPDI) or hydrogenated methylenediphenyl isocyanate (HMDI). The polyether polyols are hydrophilicpolyoxyalkylenes with a minimum of 40 mole % ethylene oxide.Isocyanate-capped polyether prepolymers which have been found to besuitable for use in the practice of the present invention includewithout limitation prepolymers commercially available or can bemanufactured. Other suitable polyols are polyester polyol,poly(ether-co-ester) polyol, poly(ether-co-hydrocarbon) polyol,poly(ether-co-siloxane) polyol, poly(ester-co-siloxane)polyol,poly(ether-co-carbonate) polyol, poly(ester-co-carbonate) polyol,poly(ester-co-hydrocarbon) polyol, polycarbonate polyol, hydrocarbonpolyol, polysiloxane polyol, poly(carbonate-co-hydrocarbon) polyol,poly(carbonate-co-siloxane) polyol, poly(hydrocarbon-co-siloxane)polyol, or mixtures thereof.

[0173] Hydrophilic polyurethane coatings can also be prepared fromsolvent systems as well as water. For solvent borne coatings, the linearpolyurethane is first dissolved in the appropriate solvent, such astetrahydrofuran, N-methylpyrolidone, dimethyl formamide,dimethylacetamide, etc. at concentrations from about 1 to 40 wt % solidsand preferably in the 1 to 10 wt % solid. Coatings are then simply caston a suitable substrate and heated (atmospheric pressure or a vacuum) toevaporate the solvent, leaving a coating of the polyurethane.Alternatively as described before, solvent borne coatings may beprepared by the prepolymer method by dissolving a urethane prepolymer inthe suitable solvents such as tetrahydrofuran, N-methylpyrolidone,dimethyl formamide, dimethylacetamide as well as a number of aromaticsolvents, such as toluene, xylene, etc.). Chain extenders and/orcrosslinkers and catalyst are then added, stirred in and coatings cast.They are then heated to both evaporate the solvent as well as chainextend/crosslink (cure) the polyurethane. Higher concentrations may beused, up to over 50% by weight of solids. Coatings may also be formed ina similar fashion bye first dissolving the polyol, chain extender,crosslinker and catalyst in solvent and then adding the isocyanate,followed by casting and curing. High concentrations are also possiblewith this method.

[0174] Polyurethane coatings may also be prepared from water-basedsystems (dispersions). Polyurethanes used are ionomers (cationic oranionic) or, less often, from poly urethanes containing hydrophilicchains. Cationic ionomers are synthesized by the reaction ofisocyanate-terminated prepolymers with tertiary amines containinghydroxyl groups, followed by quaternization of the tertiary nitrogenatom with, for example, methyl sulphate, alkyl chlorides, benzylchloride, etc. This is then dispersed in water. Anionic ionomers aresynthesized by the reaction of isocyanate-terminated prepolymers withsalts of carboxylic or sulfonic acids which incorporate two reactivegroups, amine or hydroxyl. The acid groups are first converted intosalts to prevent their reaction with isocyanate. The resulting ionomeris also dispersible in water. Alternatively, if anionic ionomers areprepared using carboxylic acids with amine groups, the reaction may becarried out in water (the amine groups will react with the isocyanategroups much faster than does water). Typical concentrations are in therange of 30-60% solids. In one embodiment the hydrophilic film orcoating for the internal surfaces of the hydrophobic elastomericmaterial that is used to fabricate the hydrophobic scaffold or theimplant of this invention can be made from flowable polymeric materialsuch as a polymer solution, emulsion, microemulsion, suspension,dispersion, a liquid polymer, or a polymer melt. For example, theflowable polymeric material can comprise a solution of the polymer in avolatile organic solvent. The coating or the film can have additionalcapacity to transport or bond to active ingredients that can then bepreferentially delivered.

[0175] In one embodiment, the polymeric material can comprise athermoplastic elastomer and the flowable polymeric material can comprisea solution of that thermoplastic elastomer that can also be biodurable.In another embodiment, the polymeric material can comprise asolvent-soluble biodurable thermoplastic elastomer and the flowablepolymeric material can comprise a solution of that solvent-solublebiodurable thermoplastic elastomer. The solvent can then be removed orallowed to evaporate to solidify the polymeric material into a film orcoating. Solidifying the polymeric material into a film or a coating canbe optionally assisted by vacuum and/or heating to a temperature belowthe softening temperatures of the polymer or of the substrate material.If sufficiently volatile, the solvent may be allowed to evaporate off,e.g., overnight.

[0176] In one embodiment, solvents are biocompatible and sufficientlyvolatile to be readily removed. The solvent or solvent blend for thecoating solution is chosen with consideration given to, inter alia, theproper balancing the viscosity, deposition level of the polymer, wettingrate and evaporation rate of the solvent to properly coat on elastomericmatrix that is used to fabricate the implant of this invention, as knownto those in the art. In one embodiment, the solvent is chosen such thepolymer is soluble in the solvent. In another embodiment, the solvent issubstantially completely removed from the coating. In anotherembodiment, the solvent is non-toxic, non-carcinogenic andenvironmentally benign. Mixed solvent systems can be advantageous forcontrolling the viscosity and evaporation rates. In all cases, thesolvent should not preferably react with the coating polymerSuitablesolvents, depending, of course, upon the solubility of the polymer,include THF, DMF, DMAC, DMSO, dioxane and N-methyl-2-pyrrolidone ortheir mixtures thereof. Additional suitable solvents will be known tothose skilled in the art.

[0177] Furthermore, one or more coatings may be applied by contactingwith a film-forming biocompatible polymer either in a liquid coatingsolution or in a melt state under conditions suitable to allow theformation of a biocompatible polymer film. In one embodiment, thepolymers used for such coatings are film-forming biocompatible polymerswith sufficiently high molecular weight so as to not be waxy or tacky.The polymers should also adhere substantially to the hydrophilic solidphase of the reticulated elastomeric matrix that is used to fabricatethe implant. In another embodiment, the bonding strength is such thatthe polymer film does not crack or dislodge during handling ordeployment of the implant.

[0178] The coating on the outer surface can be made from a biocompatiblepolymer, which can include be both biodegradable and non-biodegradablepolymers. The coating on elastomeric matrix that is used to fabricatethe implant of this invention can be applied by, e.g., dipping orspraying a coating solution comprising a polymer or a polymer that isadmixed with a pharmaceutically-active agent. In one embodiment, thepolymer content in the coating solution is from about 1% to about 40% byweight. In another embodiment, the polymer content in the coatingsolution is from about 1% to about 20% by weight. In another embodiment,the polymer content in the coating solution is from about 1% to about10% by weight. In another embodiment, the layer(s) and/or portions ofthe outermost surface not being solution-coated are protected fromexposure by covering them during the solution-coating of the outermostsurface.

[0179] Suitable film-forming biodurable biocompatible non-biodegradablepolymers to be used for hydrophilic coating include polyamides,polyolefins (e.g., polypropylene, polyethylene), nonabsorbablepolyesters (e.g., polyethylene terephthalate), silicones,poly(meth)acrylates, polyesters, polyalkyl oxides (e.g., polyethyleneoxide), polyvinyl alcohols, polyethylene glycols and polyvinylpyrrolidone, as well as hydrogels, such as those formed from crosslinkedpolyvinyl pyrrolidinone and polyesters. Other polymers, of course, canalso be used as the biocompatible polymer provided that they can bedissolved, cured or polymerized. Such polymers and copolymers includepolyolefins, polyisobutylene and ethylene-α-olefin copolymers; acrylicpolymers (including methacrylates) and copolymers; vinyl halide polymersand copolymers, such as polyvinyl chloride; polyvinyl ethers, such aspolyvinyl methyl ether; polyvinylidene halides such as polyvinylidenefluoride and polyvinylidene chloride; polyacrylonitrile; polyvinylketones; polyvinyl aromatics such as polystyrene; polyvinyl esters suchas polyvinyl acetate; copolymers of vinyl monomers with each other andwith α-olefins, such as etheylene-methyl methacrylate copolymers andethylene-vinyl acetate copolymers; acrylonitrile-styrene copolymers; ABSresins; polyamides, such as nylon 66 and polycaprolactam; alkyd resins;polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins;polyurethanes; rayon; rayon-triacetate; cellophane; cellulose and itsderivatives such as cellulose acetate, cellulose acetate butyrate,cellulose nitrate, cellulose propionate and cellulose ethers (e.g.,carboxymethyl cellulose and hydoxyalkyl celluloses); and mixturesthereof.

[0180] Suitable film-forming biodurable biocompatible biodegradablepolymers to be used for hydrophilic coating include bioabsorbablealiphatic polyesters (e.g., homopolymers and copolymers of lactic acid,glycolic acid, lactide, glycolide, para-dioxanone, trimethylenecarbonate, ε-caprolactone and blends thereof). Further, biocompatiblepolymers include film-forming bioabsorbable polymers; these includealiphatic polyesters, poly(amino acids), copoly(ether-esters),polyalkylenes oxalates, polyamides, poly(iminocarbonates),polyorthoesters, polyoxaesters including polyoxaesters containing amidogroups, polyamidoesters, polyanhydrides, polyphosphazenes, biomoleculesand blends thereof. For the purpose of this invention aliphaticpolyesters include polymers and copolymers of lactide (which includeslactic acid d-, l- and meso lactide), ε-caprolactone, glycolide(including glycolic acid), hydroxybutyrate, hydroxyvalerate,para-dioxanone, trimethylene carbonate (and its alkyl derivatives),1,4-dioxepan-2-one, 1,5-dioxepan-2-one, 6,6-dimethyl-1,4-dioxan-2-oneand blends thereof.

[0181] Hydrophilic coatings or layers made from polymers such aspartially hydrophilic polyurethane is compatible with and absorbs waterwhile conventional resiliently compressible polyurethanes arehydrophobic and shed water. While their hydrophilic nature giveshydrophilic coatings such as hydrophilic partially polyurethane usefulproperties such as the ability to absorb aqueous liquids, and serve as acarrier and aqueous flow medium for biologically active agents, it alsoleads to certain deficiencies. Among these are low physical strength,poor cell size control, and relatively high densities. Furthermore, thehydrophilic layer in forms such as foam or films swells considerablyupon absorption. Hydrophobic polyurethane is compressible but does nothold liquid. With regard to the preferred composite foam materialdescribed above, the hydrophilic coating provides for the composite foamwith a hydrophilic character, while the reticulated hydrophobic foamsubstrate can provide the composite foam with physical strength andsufficiently good flow-through characteristics that characterize areticulated foam. Thus, while a hydrophilic coating may swell when itabsorbs water or another liquid, the reticulated hydrophobic scaffoldcan be sufficiently strong to maintain integrity and prevent anysignificant increase in the overall size of the composite articles dueto swelling, even when exposed to aqueous fluids for extended periods.Also, the absence of swelling enhances removal by compressing,collapsing, gripping and withdrawal.

[0182] It is understood that this method may be applied to any type ofhydrophilic material such as hydrophilic polyurethane which is supportedby a fluid permeable biodurable structural support such, for example, asfoam, woven or nonwoven fabric or networked composites ofmicrostructural elements of various forms such as rods, tubes, tubules,fusiforms, helices, cylinders, footballs, bullets, and so on.

[0183] The film-forming polymer coating or the foamed coating to coatreticulated elastomeric biodurable matrix or the scaffold of the implantof this invention can provide a vehicle for the delivery of and/or thecontrolled release of a pharmaceutically-active agent, for example, adrug or a microspheres containing drug. In another embodiment, thepharmaceutically-active agent is admixed with, covalently bonded toand/or adsorbed in or on the coating of reticulated elastomericbiodurable matrix to provide a pharmaceutical composition or byincorporating the pharmaceutically-active agent into additionalhydrophilic coatings.

[0184] In one embodiment, the coating polymer or the coating foam andpharmaceutically-active agent or microspheres containingpharmaceutically-active agent have a common solvent. This can provide acoating that is a solution. In another embodiment, thepharmaceutically-active agent can be present as a solid dispersion in asolution of the coating polymer in a solvent. Alternatively, apharmaceutically-active agent can be coated onto the foam, in oneembodiment, using a pharmaceutically-acceptable carrier. If melt-coatingis employed, then, in another embodiment, the pharmaceutically-activeagent withstands melt processing temperatures without substantialdiminution of its efficacy.

[0185] In another embodiment, a top coating can be applied to delayrelease of the pharmaceutically-active agent or microspheres containingpharmaceutically-active agent. In another embodiment, a top coating canbe used as the matrix for the delivery of a secondpharmaceutically-active agent. A layered coating, comprising respectivelayers of fast- and slow-hydrolyzing polymer, can be used to stagerelease of the pharmaceutically-active agent or to control release ofdifferent pharmaceutically-active agents placed in the different layers.Polymer blends may also be used to control the release rate of differentpharmaceutically-active agents or to provide a desirable balance ofcoating characteristics (e.g., elasticity, toughness) and drug deliverycharacteristics (e.g., release profile). Polymers with differing solventsolubilities can be used to build-up different polymer layers that maybe used to deliver different pharmaceutically-active agents or tocontrol the release profile of a pharmaceutically-active agents.

[0186] A reticulated elastomeric biodurable matrix or the scaffold ofthe implant of this invention comprising a pharmaceutically-active agentmay be formulated by mixing one or more pharmaceutically-active agentwith the polymer used to make the scaffold, with the solvent or with thepolymer-solvent mixture and foamed. In another embodiment, thecomponents, polymers and/or blends used to form the foam comprise apharmaceutically-active agent. To form these foams, the previouslydescribed components, polymers and/or blends are admixed with thepharmaceutically-active agent prior to forming the foam or thepharmaceutically-active agent is loaded into the foam after it isformed.

[0187] A preferred drug delivery implant material for use in the presentinvention is a resiliently compressible composite polyurethane foamcomprising a hydrophilic polymer foam coated on and throughout the poresurfaces of a nonabsorbable hydrophobic foam scaffold. One suitable suchmaterial is a composite polyurethane foam product as disclosed andclaimed in Thomson, U.S. Pat. No. 6,617,014, which is both compressibleand water absorbent or liquid absorbent. The hydrophobic foam providestensile strength, support and resilient compressibility enabling thedesired collapsing of the drug delivery implant for delivery andreconstitution in situ. The hydrophilic foam coated on the interior poresurfaces of the hydrophobic foam can support useful quantities of a drugfor release in situ. A particular material of this nature is identifiedby the trademark CO-FOAMJ (Hydrophilix, LLC, Portland, Me. (USA)) and isreferenced herein as the “CO-FOAMJ composite” or the “CO-FOAMJ foamcomposite”.

[0188] Useful flexible at least patrially hydrophobic polyurethane foamsand hydrophilic polymeric coatings would be known to those skilled inthe art. Representative and preferred embodiments of such porousdrug-bearing materials and composites suitable for use as implantmaterials are set forth in co-pending, commonly assigned U.S.provisional patent application Ser. No. 60/471,518, filed May 15, 2003,and U.S. provisional patent application Ser. No. 60/471,520, filed May15, 2003, both of which are incorporated herein by reference in theirentirety, especially with regard to the disclosure and teaching of suchcomposite foams and coatings.

[0189] Preferred composite foams have a composition that allowsrelatively free flow of urine through the foam implant. Additionally theresiliency of the foam composite helps retain the drug delivery implantin place as bladder 10 naturally contracts and expands.

[0190] Desired drugs may be incorporated into an implant in any suitablemanner. In a preferred embodiment an implant such as implant 42 oranother suitable shape such as a cylinder, sphere, bullet, football, orirregular shape, comprises a porous or apertured structural scaffoldcoated with therapeutic agent-bearing material that releases one or moretherapeutic agents.

[0191] The therapeutic agent or agents, or therapeutic agent-bearingstructures, may be adhered, incorporated in a hydrophilic foam or othercoating on the hydrophobic scaffold, or, possibly covalently bonded tothe hydrophobic scaffold or the coating.

[0192] More specifically, embodiments of the invention enable thedelivery of therapeutic and other biologically useful molecules frommicro drug delivery systems such as microspheres, microcapsules,microspherules and other such micropackages, liposomes, nanoparticles,biodegradable controlled release polymer matrices, and other such drugor biologic agent micropackaging systems, as are known, or may becomeknown, to those skilled in the art which are collectively referencedherein as “microspheres.” Preferred microspheres for use in theinvention can be charged with a biologically useful agent and willbiodegrade or bioerode to release the agent in a controlled manner.

[0193] The agents to be delivered may include one or more smallmolecules, macromolecules, liposomal encapsulations of molecules,microdrug delivery system encapsulation of therapeutic molecules,covalent linking of carbohydrates and other molecules to therapeuticmolecules, and gene therapy preparations. The microspheres ormicrocapsules may contain therapeutic agents, enzymes, or othercompounds for the purpose of delayed, sustained, or otherwise controlledrelease.

[0194] There are several general types of controlled release systemsthat can be employed. For example, therapeutic agent release can bediffusion controlled, meaning that the diffusion of the agent trappedwithin a polymer matrix is the rate-determining factor for the overallrelease rate. Erosion based systems also exist in which a polymerdegrades over time and releases a therapeutic agent in an amountproportional to the gradual erosion. An osmotic pumping device usesosmotic pressure as the driving force for release. A fourth system isbased on the swelling of a polymeric matrix, such as a hydrogel.Hydrogels are polymers that absorb and swell in an aqueous environment.The release of the agent is dependent on the volume increase of the gelupon swelling and is then diffusion controlled.

[0195] In a preferred embodiment, microspheres are embedded within alayer of hydrophilic polyurethane matrix or a layer or other hydrophilicdegradable and non-degradable polymer matrix or layer applied to thesurface of a reticulated polyurethane scaffold or other stable support.It is contemplated that the embedding of microspheres may be within anyhydrophilic polyurethane or other hydrophilic degradable andnon-degradable polymer, whether it is alone or applied to any stablesurface.

[0196] In one embodiment of preparing the microsphere-bearing compositefoam material of the invention, microspheres can be mixed with the freepolymer components of the hydrophilic polyurethane, in the prepolymerphase. In another embodiment embodiment of preparing themicrosphere-bearing composite foam material of the invention,microspheres can be mixed with the film or coating forming hydrophilicpolymer during the solution preparing process. In another embodiment,polyurethane, solvent, and a therapeutic agent are added as a coating,and then the solvent is evaporated, leaving behind a coating withembedded microspheres. The resultant mixture can then be used to coathydrophobic scaffold, fixedly embedding microspheres within ahydrophilic layer, as it cures. By mixing microspheres within thehydrophilic layer, a dispersion of microspheres throughout thehydrophilic layer coated on the surfaces of pores of the hydrophobicsupport can be obtained. Beneficially, microspheres are substantiallyheld in place within hydrophilic polyurethane surface layer throughcovalent or other chemical bonding, or mechanical restraint

[0197] Substantial amounts of therapeutic agent may be incorporatedwithin hydrophilic layer as compared to merely covalently binding agentdirectly to carrier. Furthermore, the inclusion of microspheres inpolyurethane coating exposes microspheres to whatever solution carrierwas immersed within or exposed to. With both an aqueous solution or alipid solution, microspheres are exposed to hydrated hydrophilicpolyurethane layer of carrier and eluted into a liquid environmentthereby allowing microspheres to be degraded and release agent in acontrolled fashion from the hydrophilic polyurethane. This is in directcontrast to covalently binding or adsorbing these drugs to thehydrophilic layer, which may result in unexpected or uncontrollablerelease of therapeutic agent. The reticulated array of struts of carrierallows quick and easy fluidic transmission of therapeutic agent. Suchtherapeutic agents may include, but are not limited to, pharmaceuticals,therapeutic substances, vaccines, prophylactics and other substancesdepending on the intended use or result.

[0198] Immobilization of microspheres in hydrophilic layer of carrier isthus achieved without adhesive. Hydrophilic layer acts as a binder andwhen the layer becomes fully hydrated, it remains attached to underlyingscaffold does not impede the release of drugs or compounds frommicrospheres as they degrade, or utilize another mechanism to release anagent over time, based on their own internal characteristics.

[0199] The composition of hydrophilic layer is selected for itspermeability to the particular agent being dispersed by the invention.Such materials are well-known. Such materials are generally of amolecular structure which includes interstices, i.e., pores or voids,large enough to quickly allow absorption and relatively free movement ofwater molecules through the hydrophilic materials. In addition, inaccordance with the invention, the material, of which hydrophiliccoating is made, should have interstices large enough to allowtransmission of agent being dispersed, typically as a solution in anaqueous medium that has permeated contents of the bladder in thecoating, for example, the case of a medication dispersing from device 10situated in the human bladder.

[0200] Delivering agent locally generally results in a very small amountof agent being required to treat a specific location within the tissue,which has substantial benefits, such as less side effects. Smaller dosesof agent will minimize the need to replace the device as often and willreduce the systemic effects that result from large drug doses as well asthe effects that the agents will have on normally functioning tissue.

[0201] When the hydrophilic coating is in an aqueous medium, liquid ispermeated throughout hydrophilic coating and its surroundingmicrospheres, and microspheres are working in an aqueous medium.Hydrophilic layer largely has the characteristics of a hydrogel. Thus inthe case of microspheres which release agent in response to degradationof their cores, water in coating causes the characteristic hydrolyticactivity of the aqueous phase, which degrades microspheres and releasestherapeutic agent in a controlled fashion.

[0202] The system can potentially allow the storage and immobilizationof a large quantity of therapeutic agents within the hydrophilic layerof polyurethane, possibly a greater quantity than could be readilyloaded into a similar volume or weight of hydrophilic polyurethanealone, without a hydrophobic polyurethane scaffold, simply by adsorptionor covalently bonding of the agent to the material. Furthermore, theencapsulation of the microspheres by hydrophilic polyurethane may notsubstantially change the microsphere release properties becausehydrophilic layer can be expected to become fully hydrated and theequivalent of a hydrogel for that purpose to allow for fluid transportwithout losing its integrity.

[0203] When a coating or therapeutic agent carrying matrix ishydrophilic, it will absorb water and it will eventually degradebiogradable components of microspheres and release therapeutic agents ata controlled rate. Large amounts of these microspheres may be stored inthe hydrophilic layer of carrier with microspheres that are programmedto release therapeutic agent in a controlled fashion. Depending on theintended use, hydrophilic layer may be filled to varying degrees, fromvery few to fully packed with microspheres for the purpose of deliveryof therapeutic agents.

[0204] The preferred composite foam carrier uses hydrophobic layer as aphysical, three-dimensional, reticulated, flow-through scaffold forsupport and for storage of additional microspheres or other material inpores. Preferably, there is little or no reaction of the agent inmicrosphere until it is released to perform its function. Accordingly,the preferred composite foam scaffolding is an inert support structure.The hydrophobic layer may be enhanced by addition of other materials,including polymers, which enhance its desirable properties.

[0205] An advantage of using preferred composite foam or anotherreticulated foam for a scaffold is that because of its open flow-throughcharacteristic, the compounds are released from microspheres over theentire internal and external surface area of the preferred compositefoam and are available to be dispersed within any solution that passesthrough the material. This is in contrast to a conventional hydrophilicpolyurethane, which has relatively poor flow-through characteristic andrelatively poor mechanical integrity. As a result, in that setting,microspheres embedded within the center of the hydrophilic polyurethane,which release their therapeutic agent, requires diffusion of thattherapeutic agent through the entire mass of the hydrophilicpolyurethane to reach the surface and then be dispersed within thesolvent. This is because hydrophilic polyurethane does not have areticulated open-cell structure. Thus a larger amount of therapeuticagent can be delivered through device 10 over a longer period of time ascompared to alternative structures.

[0206] Since microspheres degrade and release a therapeutic agent oragents (for example, drops or other water soluble agents) intohydrophilic layer from which they exit the carrier, the concentration ismost intense at the surface of preferred composite foam. This may beparticularly useful with respect to surface applications of therapeuticagents for the purposes of wound healing or intravaginal therapeuticagent delivery, or other mucosal therapeutic agent delivery.

[0207] Microspheres allow a highly concentrated solution of agent to bedispersed in comparison with systems where the same therapeutic agent orthe same chemical is either absorbed or embedded or by desiccationconcentrated it in the hydrophilic layer. Furthermore, in absorption orabsorption or embedding of a compound in a hydrophilic layer, therelease kinetics are dramatically different then from the releasekinetics of microspheres. Without microspheres, the release kineticsgenerally comprise a first order release, a dramatic drop-off, and thenan additional drop off to zero over a period of time. By usingmicrospheres, agent release can be more accurately controlled by usingmicrospheres with different release characteristics.

[0208] Microsphere release of a therapeutic agent has certain advantagesas compared to release directly by a foam. For example, such releaseavoids the uncertainties created by degradation of composite foam or thedegradation of an adhesive over a period of time, pH variation at thedelivery site, or movement of the foam.

[0209] A device of the invention is useful for a number of applications.Specifically, a device may be inserted into a bodily cavity and placednext to or even shaped around various types of indwelling devices, suchas heart valves, pacemakers, artificial joints, intravenous orintraarterial catheters or devices that are inserted into the bodycavity such as gastrointestinal tubes, intrauterine devices, ordiaphragms. Microspheres can also be triggered to release biologicallyactive agents when the pH of the environment turns either acidic orbasic. This change in pH may be due to changes occurring naturally inthe environment or changes artificially induced. Urinary catheters,including Foley catheters and catheters that have no balloon, andureteral stents, may be used according to this disclosure to preventurease activity or prevent bacterial infestation. The device would beplaced in an environment where aqueous solution (such as blood) orlipids pass through pores.

[0210] In an alternative embodiment, the inventive device comprises acontrolled release formulation comprising microspheres of a vaccinesuspended in a hydrophilic polymer matrix for delivering appropriateantigens for immunization against an infectious disease. In traditionalmethods, the efficiency of such vaccines often is low because of rapiddegradation of antigens and their very short in-vivo half lives. Thus,large doses have been required to achieve adequate local concentrations.An advantage of the microencapsulation is that it protects the potencyof weak antigens such as the small synthetic or recombinant peptides ofHIV. Another advantage is that it may, by virtue of the improveddelivery of antigen to the immunologic system, enhance the speed, rigorand persistence of the immune response. A further advantage may bemodulation of antibody avidity, specificity, quantity, isotype andsubclass. Furthermore the amount of antigen needed to provide effectiveprotection may be decreased, thereby decreasing the cost of thevaccines. Additionally, the microspherical delivery form of the vaccinepursuant to the invention, may be more efficacious than a conventionalaqueous vaccine.

[0211] In general, the quantity of therapeutic agent and themicropackaging, if employed, are selected according to the anticipatedrate of elution from an implant according to the invention to provide adesired dosage throughout the intended implant period. The therapeuticagent-supporting capacity of an implant may be varied by varying itsmass within a given external periphery, for example, by varying thethickness of an implant such as implant 42 as determined by the spacingbetween the inner and outer surfaces 52 and 54, or by changing the shapeof inner surface 52 or by increasing the temperature or enlarging thesize.

[0212] If desired, measures may be taken to modify the gross density ofimplant 42 to render it buoyant in urine, so that it will tend tomigrate upwardly in bladder 10, away from trigone 22, when the host isupright. For example the material or materials employed to fabricate animplant such as implant 42 may be selected to provide an implant of adesired gross density. The term “gross density” is used to refer to theoverall density of the implanted product, referring to its displacementin water.

[0213] Alternatively density control materials, such for example,EXPANCEL7 gas filled microspheres, available from the Casco Productsunit Akzo Nobel, may be included in the structure of an implant.

[0214] The implant according to the invention may be of any suitablesize and will normally be sized according to the target implantationsite. For example, an intravesicular implant may have a major and/orminor diameter in the range of from about 0.5 to about 12 cm, preferablyabout 3 to about 8 cm, and more preferably about 4 to about 6 cm. Height46, as a proportion of a diameter may lie in the range of from about 0.1to about 1.0, preferably about 0.2 to about 0.6, more preferably about0.4 to about 0.5 cm.

[0215] In a preferred embodiment of the invention the biologicallyactive substance is covalently bound to the hydrophilic material. Thedegradable hydrophilic material will be absorbed nearby, causing it todegrade by hydrolysis in a predictable fashion. This hydrolysis reactionmay create a relatively acidic environment within bladder 10 which canbe useful in reducing calcification, the formation of stones and thelike.

[0216] Therapeutic Agents and Therapies

[0217] The invention also provides therapeutic agent delivery implantsloaded with complex therapeutic agent formulations which may comprise,for example, one or more active therapeutic agents together with one ormore adjuvants to facilitate the performance of at least one of thetherapeutic agents. For example, an absorption enhancing ingredient mayby included with a therapeutic agent intended for systemicadministration to enhance the transport of the therapeutic agent throughthe bladder wall to the plasma. References to therapeutic agents hereinare intended to include one or more therapeutic agents as well as suchtherapeutic agent formulations, unless the context indicates otherwise.

[0218] The amount of pharmaceutically-active agent present depends uponthe particular pharmaceutically-active agent employed and the medicalcondition being treated. In one embodiment of the invention, thepharmaceutically-active agent or microspheres containingpharmaceutically-active agent are present in an effective amount. Inanother embodiment, the amount of pharmaceutically-active agent ormicrospheres containing pharmaceutically-active agent represent fromabout 0.01% to about 60% of the coating by weight, based upon the totalweight of the coating. In another embodiment, the amount ofpharmaceutically-active agent or microspheres containingpharmaceutically-active agent represents from about 0.01% to about 40%of the coating by weight, based upon the total weight of the coating. Inanother embodiment, the amount of pharmaceutically-active agent ormicrospheres containing pharmaceutically-active agent represent fromabout 0.1% to about 20% of the coating by weight, based upon the totalweight of the coating.

[0219] Any suitable weight proportion of therapeutic agent may be used,based upon the weight of the implant exclusive of the therapeutic agent.The proportion of therapeutic agent to non therapeutic agent implantmaterial may vary, for example, from about 0.01 to about 40 percent byweight, preferably from about 0.1 to about 10, based upon the totalweight of the implant.

[0220] The hydrophilic foam coating can bear any one or more of avariety of therapeutically useful agents, for example, agents that canaid in the healing of bladder 10 and the reduction of urgency, such asoxybutynin, or other anticholinergic agents. Furthermore the hydrophilicfoam, or other drug immobilizing means, can be used to carry genetictherapies, e.g., for replacement of missing enzymes, to treatcystopathies at a local level, and to release palliative agents. Morebroadly, a useful therapeutic agent can be any compound that isbiologically active and requires short or long term administration to atissue or organ for maximum efficacy. Therapeutic agents that can beused in accordance with the present invention include, but are notlimited to, antibiotics, antimuscarinic agents, anticholinergic agents,antispasmodic agents, calcium antagonist agents, potassium channelopeners, musculotropic relaxants, antineoplastic agents, polysynapticinhibitors, and beta-adrenergic stimulators. Examples of anticholinergicagents are propantheline bromide, imipramine, mepenzolate bromide,isopropamide iodide, clidinium bromide, anisotropine methyl bromide,scopolamine hydrochloride, and their derivatives. Examples ofantimuscarinic agents include, but are not limited to, hyoscyaminesulfate, atropine, methantheline bromide, emepronium bromide,anisotropine methyl bromide, and their derivatives. Examples ofpolysynaptic inhibitors include baclofen and its derivatives. Examplesof .beta.-adrenergic stimulators include terbutaline and itsderivatives. Examples of calcium antagonists include terodiline and itsderivatives. Examples of musculotropic relaxants include, but are notlimited to, dicyclomine hydrochloride, flavoxate hydrochloride,papaverine hydrochloride, oxybutynin chloride, and their derivatives.Examples of an antineoplastic agents include, but are not limited to,carmustine levamisole hydrochloride, flutamide,(w-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]), adriamycin,doxorubicin hydrochloride, idamycin, fluorouracil, cytoxan, mutamycin,mustargen and leucovorin calcium. Examples of antispasmodic agents arehexadiphane, magnesium gluconate, oktaverine, alibendon, butamiverine,hexahydroadiphene, 2-piperidinoethyl 3-methylflavone-8-carboxylate,4-methylumbelliferone 0,0-diethyl phosphorothiate. Examples of potassiumchannel openers include pinacidil andN-[-2-Nitrooxy)ethyl]-3-pyridinecarboxamide.

[0221] Additionally, a potential significant use of the therapeuticagent delivery implant is as a delivery system for chemotherapeuticagents to treat bladder cancer. The therapeutic agent delivery implantof the present invention, can with a, single application, deliver asustained dose of chemotherapeutics to the mucous membrane of thebladder 10 for periods of up to about 28 days, at which time an implantsuch as implant 42 can be replaced with a fresh therapeutic agent-ladenimplant, if desired. By delivering the therapeutic agent continuously tothe tumor, more of the tumor cells can be exposed to the therapeuticagent during their proliferative phase when they are most sensitive tothe chemotherapy. Additionally, the dose of the therapeutic agents canbe kept lower then in the usual interrupted, short-term treatment, thusminimizing irritation and discomfort to the patient. Further, the factthat one minor procedure is needed for insertion and one for removalprovides less inconvenience to the patient and better cost efficiencythen with the usual interrupted, short-term treatment.

[0222] Therapeutic agents that do not readily cross to the plasmabarrier offered by the wall of the urothelium may be employed for localusage, for example, to treat bladder-related conditions, whiletherapeutic agents that readily cross to the plasma barrier may besystemically administered via bladder implantation of the implants. Sometherapeutic agents may have dual functionality, being locally useful andalso being systemically absorbable.

[0223] The therapeutic agent delivery implant can be useful in thedelivery of antibiotics to the urinary tract, and especially bladder 10.The present invention provides methods of treating such cases comprisingimplantation of a therapeutic agent delivery implant, such as implant42, containing an antibiotic which is inserted into bladder 10 as aprophylactic measure to preempt possible urinary tract infection. Thetherapeutic agent delivery implant can be replaced on a regular basis,in one embodiment of the present invention approximately monthly orevery twenty-eight days. Other replacement periods may be employed, ifdesired, for example, from about 7 days to about two months, morepreferably from about two to about six weeks. Toward two months problemsarising from encrustation and the like may be expected.

[0224] Further, the therapeutic agent delivery implant can deliverantibiotics for the treatment of systemic chronic infections. Forexample, diseases such as Lyme Disease, tuberculosis, or evenperiodontitis require the long-term administration of antibiotics,sometimes for as long as six months to years. Some diseases also requirethe long-term treatment using intravenous antibiotics requiring doctorvisits or skilled nursing care. Often a special catheter needs to besurgically inserted into a vein or under the skin. The inventiveimplants can be inserted into the bladder 10 and may be changed aboutonce a month under a local anesthetic greatly ameliorating theseproblems.

[0225] Some other therapeutic agents that may be delivered to thebladder include antispasmodics to treat overactive or spastic bladderswith desensitizing or antispasmodic agents. Overactive bladder andspastic bladder conditions area significant problem, and the possibilityof placing an implant such as domical implant 42 in the bladder thatdoes not impinge on the bladder neck (the dome-shaped implant) whileallowing the chronic delivery of a desensitizing agent for comfort or anantispasmodic agent is another benefit of the invention.

[0226] In addition, systemically acting therapeutic agents may bedelivered by the implants of the invention. There are many therapeuticagents that require injection on a regular basis, for example, growthhormone. Proteins of which growth hormones are exemplary are fragile andcannot be taken orally due to destruction in the stomach due to theaction of stomach acid and of proteolytic enzymes. Accordingly, they aredelivered by daily injection. Such daily injections can be entirelyavoided or reduced by delivering such labile therapeutic agents throughthe bladder mucus membrane employing the implants of the presentinvention.

[0227] In use, the health care provider can, if desired, determine thesize of the desired therapeutic agent delivery implant according to theinvention by imaging the bladder, such as by radiography or ultrasound.Optionally, an implant can come in a single size that expands to fit abladder. An implant would have at least one desired biologically activecompound added either at the site of insertion, or come prepackaged withthe compound or compounds. The implant would then be compressed andloaded into a tubular structure, such as a trocar, cannula, fiberopticcannula, catheter, or minimally invasive rigid or flexible scope, suchas a cystoscope, or the like. Alternatively, the implant can comeprepackaged in a tube that fits into an insertion device, such as acystoscope. The insertion device would then be threaded up the urethra30 into bladder 10, optionally with the use of a topical anesthetic.Once in bladder 10, the implant would then be released from the tubularstructure into a bladder 10, preferably away from the trigone 22. In onemethod, the implant would be released into the dome of bladder 10, awayfrom the trigone to prevent undesirable reactions at the trigone andkeep the implant away from the ureters. Once the therapeutic agent isused up, the implant can be removed, usually after a cycle of from about2 to 8, preferably about 4, weeks to prevent any risk of an immuneresponse to the foreign object. Additionally, if long term treatmentwith successive application of therapeutic agent delivery implants isdesired, the spent therapeutic agent delivery implant should be removedwhen the fresh therapeutic agent delivery implant is implanted to avoidadversely impacting the urine retaining capacity of bladder 10, andother potential problems.

[0228] If removal is necessary, a removal instrument such as a trocar,cannula, fiberoptic cannula, catheter, or minimally invasive rigid orflexible scope, such as a cystoscope, or the like, can be inserted intothe bladder 10, used to grip a portion of the implant which may then bepulled into the removal instrument, thus compressing the implant forremoval. The removal instrument can have a hook, grasping forceps orother similar device that grabs a piece of the therapeutic agentdelivery implant.

[0229] Alternatively, implant 70 can have attached to it a cord 72 whichextends externally from the urethra, as shown in FIG. 4, then, when thebiologically active substance is exhausted, cord 72 can be pulled intothe cystoscope enabling implant 70 to be drawn into the instrument andcompressed for removal through the urethra.

[0230] Some of the above-described benefits, and others, of the novelhemispherical or domical implants and implant systems, such as implant42, that are provided by the invention can be summarized as follows:

[0231] Large volume. By constructing the implant as the outermost layerof a solid object approximating the shape and size of the availablevolume at the implantation site, a relatively large volume of implant ofresilient porous material can be inserted to a mammalian body site suchas bladder 10, where implant 42 can, if desired, extend around theentire superior portion of bladder 10. Such an implant may be deployedwithin the bladder and rest in the dome of the bladder, located in placeby the outward elastic compressibility of the foam, preventing theimplant from being dislodged and intruding on the bladder neck 28 andtrigone 22. Its large volume enhances capacity of the implant to bearbiological actives.

[0232] Large surface area. The hollow hemispherical or relatedconfiguration of implant 42 provides a very substantial internal surfacearea for diffusion of drugs and a large external surface area to permitaccess to, and enhance flow of ambient fluids, for example urine, to thetherapeutic agent-bearing internal surfaces.

[0233] By locating itself adjacent the walls of the implantation site,for example, bladder inner walls 12, implant 42 presents a large surfacearea in close proximity to or even in contact with the bladder mucosafor ready transfer of therapeutic agents to the bladder mucosa forsystemic absorption.

[0234] Simple shape. A hemisphere, or dome, is a simple shape easilyfabricated.

[0235] Compressible. A hemisphere, or dome, rendered in low bulk densityreticulated resilient foam lends itself to being compressed and loadedwithin an introducer cannula, cystoscope or the like.

[0236] Obstruction-free. Even if the foam material were to cover ureteropenings 25, 27, the openings would not be obstructed because the porousmaterial of the implant can permit urine flow.

[0237] Self-locating. A particularly significant benefit of implant 42is a natural ability of the domical shape of the implant to remainstable and in place against the dome of the bladder, preventing theimplant form floating freely in the contents of the bladder and avoidingcontact with the trigone 22.

[0238] Durability. Employment of a foam composite implant materialhaving a durable hydrophobic polyurethane, or possibly a polycarbonatescaffold provides an implant that can be inserted for extended periods,e.g., up to 28 days, if desired, without degrading into fragments orparticles that could cause blockage of functional biological structuressuch as ureters 25, 27 or urethra 30. In some cases, longer or evenpermanent implantation may be possible.

[0239] High dosage. Shell-like implants such as domical implant areadvantageous in being able to release therapeutic agents or other activeagents at a relatively high dosage, albeit for a relatively short periodof time. The large external surface area and thin wall constructionpromote flow-through and drug elution.

[0240] Therapeutic Agent Packaging

[0241] The therapeutic agents to be delivered by the implants andmethods of the invention may be suitably packaged, for example, to havedesired release characteristics, for secural to the implants of theinvention. Advantageously, such packaging may comprise degradablemicrospheres or microcapsules.

[0242] One such controlled release formulation comprises biodegradablepolymer microspheres containing an biologic active agent whichmicrospheres are secured to a hydrophobic foam scaffold for example, byadhesive or by being retained in a layer of hydrophilic polymer matrix,e.g., a hydrophilic polyurethane foam coating the scaffold pores.

[0243] The hydrophilic polyurethane layer can act as both a reservoirand a carrier. The carrier immobilizes the microspheres and allows themicrospheres to release a material at a controlled rate or rates or at acontrolled release time or times at a specific site. By avoiding use ofa conventional adhesive, the release kinetics can be enhanced, byavoiding interference from the degradation of an adhesive. Themicrospheres can comprise a solution, solid gel or other formulation ofthe biologic agent contained in a semipermeable housing with controlledwater permeability.

[0244] Introducer Instruments

[0245] Various introducer instruments, for example, cannulae, trocars,catheters, or minimally invasive rigid or flexible instruments,optionally one incorporating visualization or electromechanics, such asa cystoscope, laproscope, arthroscope, or endoscope, or the like, may beemployed to introduce the implants of the invention to desired mammaliancorporeal sites, and to remove the implants, if desired, as will beapparent to those skilled in the art. Some suitable instruments areillustrated, by way of example, in FIGS. 16-20.

[0246] The introducer instrument shown in FIG. 16, that is, rigidcystoscope 200, comprises a body 202 having a hand grip 204 formanipulating the cystoscope and a hollow shaft 206 extending from body202. The proximal end 208 of the cystoscope body 202 is provided withportals (not shown) to receive various instruments, for example, acatheter or forceps, or connections for services such as suction, gasand/or water, as well as a viewing portal. Older cystoscopes employtelescope-like optical arrangements for viewing the work site, but morerecent cystoscopes employ fiber optics and output an image to a videomonitor. The tip 210 of cystoscope 200 generally contains portalsthrough which the various instruments or services employed, as well asviewing devices such as fiber optics, may be passed.

[0247] Hollow shaft 206 of cystoscope 200, as shown in FIG. 16, issubstantially rigid so that the relevant anatomy has to be substantiallyaligned for hollow shaft 206 to be inserted through the urethra todeliver an implant to the bladder.

[0248] The flexible cystoscope 220 shown in FIG. 17 has similarcomponents to the rigid cystoscope of FIG. 16, as indicated by use ofthe same reference numerals, with the difference of a flexible hollowshaft 222 in place of rigid shaft 206 and an optional winder mechanism224. Winder mechanism 224 can be rotated to move the distal tip 226 offlexible shaft 222 from side to side. Cystoscopes employing othermechanisms, for example, joystick-like controls actuating miniaturemotors enabling a variety of movements of the cystoscope tip 226 mayalso be used.

[0249] Cystoscope 200 can be employed to deliver an implant to thebladder by inserting flexible shaft 222 into the urethra, withoutrequiring anatomical alignment.

[0250] The catheters illustrated in FIGS. 18 and 19 are two examples offorceps-equipped catheters that can be employed for implantation andretrieval of implants in accordance with the present invention. As shownin FIG. 18, catheter 230 comprises, at its proximal end, a scissor-likeactuation mechanism 232, a hollow shaft 234 that contains a linkage 236,and an end tool, in this case forceps 238 that can be projected throughthe distal end 240 of catheter 230. Forceps 238 are shown in aretracted, closed position where they can grip an implant (not shown)within catheter 230.

[0251] Actuation mechanism 232 comprises a pair of scissor blades 242,244, pivoted together at 246, of which blade 242 is attached to cathetershaft 234 and blade 244 is attached to linkage 236. Each blade 242, 244bears a handle 248, 250 respectively. Manipulation of handles 248, 250operates through linkage 236 to actuate forceps 238 which can grasp andrelease an implant such as implants 42, 80, 90, 94, 96, 100, 110 or 120,to draw the implant into catheter 230 and expel it therefrom forinsertion at, or removal from, a particular body site.

[0252] The catheter 260 illustrated in FIG. 19 has a modified,syringe-style actuation mechanism 262 comprising a plunger 264 andfinger rests 266 and 268 either side of plunger 264. Parts with the samereference numerals are similar to those of catheter 230, as shown inFIG. 18. Forceps 238 is shown in an advanced, opened position afterreleasing an implant or preparatory to grasping an implant.

[0253] As shown in to FIG. 20, a modified end mechanism for a cathetersuch as catheter 230 shown in FIG. 18, comprises a sleeve 270 insertedinto a catheter end 272. An implant such as implant 90, in compressedconfiguration, can be contained within sleeve 270 in catheter end 272.Implant 90 can be compressed and assembled into sleeve 270 prior toinsertion into catheter end 272 and could be supplied in this form by avendor, facilitating the medical practitioner's procedure. Catheter end272 has an inwardly facing peripheral retainer lip 274 that can engageand retain sleeve 270 so that when the end mechanism is actuated,implant 90 is expelled from the catheter and sleeve 270 remains withinthe catheter.

[0254] Treatment Methods of the Invention

[0255] The invention also provides treatment methods utilizing the novelimplants described herein which may be utilized in combination withsuitable introducer instruments, as described hereinabove. Thecombination of an expansible implant, as described herein, bearing abiological active to be delivered in situ, and retained in an introducerapparatus in compressed configuration provides a novel implantationapparatus useful for a variety of treatments of mammals, especiallyhumans, according to the nature of the biological active.

[0256] Thus, the invention provides a treatment method comprisinginserting an introducer instrument, charged with one or more implants incompressed configuration and bearing one or more biological agents, eachas described herein, into a mammalian corporeal site, for example thehuman bladder, and releasing the implant or implant at the corporealsite. The implant expands at the site, opening up its pores orinterstices to passage of ambient body fluids, e.g., urine which canelute the one or more biological agents from the implant for local orsystemic use. If necessary, protective coatings or embedding materialaround the biological active may be eroded away by the ambient bodyfluid.

[0257] The treatment methods can also optionally include any one or moreof the following elements: removing the implant from the treatment siteat the end of a treatment period utilizing a suitable instrument;loading the implant into an introducer instrument; compressing theimplant; and manipulating the implant in situ to a desired position,orientation or configuration employing a suitable instrument; as well asimaging the implantation site and selecting a suitable implant accordingto the characteristics of the site image.

[0258] Therapeutic Compositions

[0259] The invention also provides a range of novel therapeuticcompositions that can be effected employing the novel implants of theinvention. A simple composition comprises an effective quantity, for theintended implantation period and therapy, of a primary biologic agentintended to treat a condition. The quantity can be varied according towhether the biologic agent is to be utilized locally, e.g., in thebladder, or systemically after transmission across the bladder mucosa tothe plasma. Any suitable and effective quantity can be supported on oneor more implants to constitute an individual treatment.

[0260] In one embodiment of the invention, the quantity corresponds withthe quantity required to provide a desired average local concentrationof the particular biologic agent, in accordance with its known efficacy,within the bladder, or other site, for the intended period ofimplantation, e.g., 7, 14, 28, or 42 days.

[0261] In another embodiment of the invention, the quantity correspondswith the quantity required to provide a desired concentration of theparticular therapeutic agent, in accordance with its known efficacy, inthe bloodstream for the intended period of implantation, e.g., 7, 14,28, or 42 days. In either case, due allowance can be made for losses dueto urination, for example from ten to fifty percent loss allowance couldbe made depending upon the individual patient and their routines.

[0262] In addition to a primary therapeutic agent, or therapeutic agentintended to treat a condition, for example, infection or tumor growth,one or more auxiliary therapeutic agents may be included in thetherapeutic composition. Such auxiliary therapeutic agents can performone or more of various supplemental roles. For example, one such role istolerance enhancement to enhance the patients tolerance of the implantsystem. Another useful role is membrane permeability enhancement, ormembrane solubilization, to facilitate transport of the primarytherapeutic agent across the bladder mucosa to the plasma for systemicutilization or delivery of the primary therapeutic agent. Other usefulroles and therapeutic agents or other agents that may fulfil them and beemployed in the therapeutic compositions of the invention will beapparent to those skilled in the art.

[0263] Therapeutic agents or pharmaceuticals useful for toleranceenhancement are intended to modulate the responses of local biologicstructures in the vicinity of the implant to the presence of theimplant, or to contact with the implant or of responses to implantelutants to reduce undesired micturition, urination or incontinence orto ameliorate discomfort, irritation or pain.

[0264] Some useful such a therapeutic agents include, by way of example,antispasmodic drugs, for example, oxybutinin, and agents affecting theafferent nerves for mechano-receptors, specifically the c-fiberafferents and agents which block the vanilloid receptor subtype 1(VR1).A representative therapeutic agent having such capability is capsaicinwhich can be employed at an effective dosage, as described in connectionwith the primary agent, for example, a dose in the range to provideconcentrations within the bladder of from about 1 mg/kg to about 45mg/kg or from about 0.1 mM to about 10 mM. Another useful drug isresiniferatoxin, which affects dorsal root mechano-chemo receptors in adesensitization manner. A suitable dosage range is from about 1 nM to1000 nM, preferably from about 10 nM to about 100 nM to provide adesired slow release.

[0265] Where a the primary therapeutic agent is intended to be deliveredto the bloodstream via the bladder mucosa, a membrane permeabilityenhancing agent can be included in the therapeutic composition inquantities or concentrations to provide an effective concentration atthe relevant membrane. Some examples of suitable agents for use in thebladder are protamine sulfate and polypropylene glycol.

[0266] Among the primary therapeutic agents that may be employed includegenetic agents, preferably nonviral genetic therapy agents that canmodify local cells, for example, bladder wall cells to provide usefulresults such as the local production of insulin for the treatment ofinherited juvenile diabetes. Genetic therapy may also be provided forother hormones or factors regarding which the patient is deficient. Amembrane permeation enhancer, or solubilizer is desirably also includedto deliver the genetic therapy agent to the basal or intermediate cells.

[0267] As shown in FIG. 16, the innermost layer of the bladder wall 12,urothelium 32, as described above comprises a basal cell layer 280, anintermediate cell layer 282 and an innermost layer 284 of epithelialumbrella cells 286. The luminal surfaces of the umbrella cells 286 arecoated with a layer 288 of glycosaminoglycans and

[0268] The basal cell layer 280 is separated from the connective tissueand elastic fibers of submucous coat 34 by a basal lamina 290. Theglycosaminoglycan-coated surfaces of the umbrella cells 286 line thebladder inner walls 12 and accordingly interface with urine in thebladder. Thus, the permeability of this coated layer largely determineswhether a given substance can be systemically absorbed from the bladderand can be enhanced by therapeutic agents such as protamine sulfate orpolypropylene glycol, as described herein.

[0269] One preferred mechanism of genetic therapy comprises modificationof the intermediate cells 282 to cause them to generate insulin oranother therapeutic agent. The generated insulin or the like movestoward the basal cell layer 280 and be absorbed into the blood stream.The interstices in the intermediate cell layer 282 can provide sites forthe accumulation of such locally generated agents or agents releasedfrom an inventive implant in the bladder and transported across thebladder mucosa whence they may be steadily absorbed into thebloodstream.

[0270] Some literature of interest in connection with delivery of agentsvia the bladder includes: Fraser et al., “The Future of BladderControl-Intravesical Drug Delivery, a Pinch of Pepper, and Gene Therapy”Reviews in Urology vol. 4, no. 1 (2002); Szallasi, A., et al.,AResiniferatoxin-type phorboid vanilloids display capsaicin-likeselectivity at native vanilloid receptors on rat DRG neurons and at thecloned vanilloid receptor VR1., 1999., 128(2):, 428-434.; Macha, A., etal.; “APhorboid 20-homovanillates induce apoptosis through aVR1-independent mechanism.”, Chem. Biol., 2000, 7(7):, 483-492.Szallasi, A., & P. M. Blumberg. and AVanilloid (Capsaicin) receptors andmechanisms, Pharmacol. Rev., 1999, 51:, 159.

[0271] The individual therapeutic agent or composition may be absorbedon the implant. Alternatively, the therapeutic composition or thebiologic agent may be chemically bound to the implant, or one or morecomponents of the composition may be chemically bonded and another orothers may be chemically bound. A preferred means of immobilizing thetherapeutic composition is by micropackaging, for example, inmicrospheres, as described elsewhere herein.

[0272] Other Aspects of the Invention

[0273] In other aspects the present invention providesdevice-therapeutic agent therapy for urinary tract infections employingbioactive polymeric materials and novel polymeric matrices such as theimplants described herein, which materials are also useful inendovascular applications addressing cardiovascular, neurological, andperipheral vascular conditions. Furthermore, the invention providesbiosystems applications employing such polymeric materials and matricesand which involve the immobilization and controlled release of biologicsfor a range of clinical purposes, including, for example, withoutlimitation, use of such polymeric foam composites for non-active woundcare applications.

[0274] Pursuant to the present invention such biosystems applicationscan employ a polyurethane foam composite based on a combination of areticulated hydrophobic polyurethane scaffold and a hydrophilicpolyurethane coating, some examples of which are disclosed in Thomson,supra. A valuable functionality of the composite foam includes anability to immobilize and release therapeutic agents, high flow-throughcharacteristics, biocompatibility and immunogenicity. Tests withcollagenase demonstrate an ability to immobilize and retain enzymaticactivity within the polymer system. In addition, the composite foammaterial can support mammalian, especially but not exclusively human,cell propagation and proliferation into the polymeric matrix and thepresent invention includes cell proliferation or propagation systemsrealized in the polymeric matrices disclosed herein and in thereferences incorporated herein.

[0275] The invention also includes endovascular applications of theencompassing implantable polymeric devices delivered into the vascularsystem for interventional neuroradiological, interventionalcardiological peripheral vascular and other purposes.

[0276] Biosystems applications according to the invention can encompassextracorporeal and short-term (less than 28 days) implantable polymericdevices delivered into the gastrointestinal or intravesicular cavitiesfor the controlled release and/or sustained activity of therapeuticagents, including enzymes, especially enzymes employed for enzymetherapy of urinary tract infections.

[0277] While reference has been made herein to mammals, it will beunderstood that the inventive implants can be employed to treat otheranimal classes such for example, as birds, reptiles or the like.Particular mammals of interest are primarily humans but alsocommercially valuable species such as horses, pigs, cattle, sheep, otherprimates, dogs and cats, and the like, as well as laboratory animalssuch as mice and rats.

[0278] As an example of certain aspects of the invention, the results ofrepresnetative testing are set forth below:

EXAMPLE 1

[0279] A reticulated TDI/polyether based foam (SIF grade obtained fromFoamex) was used as a scaffold or substrate. The foam substrate was4″×4″ (10.2 cm×10.2 cm) square sample with a thickness of ¼″ or 0.635 cmwith a volume of 65.5 cm³ and weighed 1.2 g, giving a density of 0.0183gms/cc. 2.42 grams of hydrophilic polyurethane prepolymer (Urepol 1002Aobtained from Envirochem) and 64 milligrams of Thio-TEPA was diluted in6 ml of DMF. The foam was dipped into the solution mixture ofpolyurethane prepolymer, Thio-TEPA and DMF. The Thio-TEPA containingsolution mixture of polyurethane prepolymer and DMF was then distributedand spread over the foam substrate. During the spreading anddistribution, it was ensured that solution mixture contacted the foamsubstrate from all sides and coated both the surface and internal poresof the foam substrate.

[0280] The foam substrate with coated solution mixture was heldovernight below 8° C. The coating was cured by the reaction of theambient moisture with the available reactive isocyanate in theprepolymer. After the overnight curing, the foam substrate with coatedsolution mixture was vacuum-dried to remove residual solvents to leave acoating of polyurethane containing Thio-TEPA.

[0281] The final weight of the foam substrate and the drug loadedcoating was 3.24 gms. Density of the coated foam substrate was 0.0495gms/cc. The drug loading was 0.009 gms per 1 gm of coated foamsubstrate, i.e. 0.9 wt %. The drug entrapment efficiency was 50%calculated from a final measures drug loading of 0.9 wt % and atheoretical drug loading of 1.8 wt %. The weight of the drug in thefinal coated foam substrate was 0.029 gms or 29 mgs with the drugdensity on the coated foam substrate being 0.44 mgs per cc.

[0282] Conditions used in the preliminary coating experiment along withdrug loading results are presented in the following table: TABLE 1Hydrophilic Prepolymer Solution System Pre- Post- Theor. Final SolventDrug coating coating drug drug Entrapment Prepolymer added, weight, FoamSample loading, loading, efficiency, Drug Lot Number weight, g mL mg wt,g wt, g wt % wt % % Thio-TEPA J1168-027-1 2.42 6 64 1.2 3.24 1.8 0.9 50

[0283] The coated foam substrate was placed in phosphate buffer at 37 C,and a pH of 7.4 and the Thio-TEPA in vitro release was measured. Theresults are presented in the table below: TABLE 2 Core CumulativeRelease, loading, % at Day Lot No: Drug wt % 1 3 6 J1168-027-1 Thio-Tepa0.9 11.9 43.7 66.6

[0284] The polyurethane coated polyurethane foam substrate successfullydemonstrated its ability release the Thio-Tepa over a period of time orshow controlled release capabilities.

EXAMPLE 2

[0285] A cast film of polyurethane containing Ciprofloxacin was made byreacting hydrophilic polyurethane prepolymer (Urepol 1002A obtained fromEnvirochem) with distilled water. The reacting mixture was spread in athin film over a glass petri dish. The film was cured overnight anddried to leave a thin film of polyurethane containing Ciprofloxacin. Theresultant drug carrying film was further vacuum-dried. The drug loadingwas measured to be 0.06 gms per 1 gm of coated film, i.e. 6.0 wt %.

[0286] The drug carrying film was placed in phosphate buffer at 37 C anda pH of 7.4 and the Ciprofloxacin in vitro release was measured. Theresults are presented in Table below: Core Cumulative Release, loading,% at Day Lot No: Drug wt % 1 3 4 J1168-018-7 Ciprofloxacin 6.0 15.7 16.829.28

[0287] The polyurethane film successfully demonstrated its abilityrelease Ciprofloxacin over a period of time or show controlled releasecapabilities.

[0288] The entire disclosure of each patent and patent applicationcross-referenced or referenced herein and of each non-patent publicationreferenced herein is hereby incorporated herein by reference thereto, asthough wholly set forth herein. Each document incorporated by referencein any of the foregoing patents, patent applications or non-patentpublications is also incorporated herein in its entirety by referencethereto.

[0289] While illustrative embodiments of the invention have beendescribed above, it is, of course, understood that many and variousmodifications will be apparent to those of ordinary skill in therelevant art, or may become apparent as the art develops. Suchmodifications are contemplated as being within the spirit and scope ofthe invention or inventions disclosed in this specification.

We claim:
 1. A therapeutic agent delivery implant for implantation intoa patient's body, said implant comprising: a resilient or flexible, atleast partially hydrophobic reticulated elastomeric support scaffold andone or more therapeutic agents secured to and/or supported by thescaffold for release within the patient.
 2. A therapeutic agent deliveryimplant for implantation into a patient's body, said implant comprising:a resilient or flexible, at least partially hydrophobic reticulatedelastomeric support scaffold; and a hydrophilic coating arranged on saidscaffold, wherein said coating contains one or more therapeutic agentsfor release within the patient.
 3. The implant of claim 2, wherein atleast one therapeutic agent is secured to and/or supported by thescaffold.
 4. The implant of claim 1 or 2, wherein at least onetherapeutic agent is contained within microspheres.
 5. The implant ofclaim 1 or 2, wherein the scaffold is biodurable.
 6. The implant ofclaim 2, wherein at least one therapeutic agent is contained withinmicrospheres in the coating.
 7. The implant of claim 2, wherein thecoating contains enzymes.
 8. The implant of claim 1 or 2, wherein thethe scaffold comprises a hydrophobic polyurethane.
 9. The implant ofclaim 2, wherein the coating comprises a hydrophilic polyurethane. 10.The implant of claim 1 or 2, wherein the therapeutic agent is selectedfrom the group consisting of a pharmaceutical, a growth factor, anenzyme, RNA, DNA, a nucleic acid, and a vector, and mixtures of two ormore thereof.
 11. The implant of claim 1 or 2 which has a hemispherical,bullet, football, cylindrical, spherical, or irregular shape.
 12. Theimplant of claim 11 which is spaghetti-shaped.
 13. A method ofdelivering an implant to a mammalian site, which comprises the steps of:(a) collapsing and/or compressing an implant of claim 1 or 2; (b)inserting the implant from step (a) into a rigid or flexible deliveryinstrument having a distal tip; (c) advancing the delivery instrumentdistal tip to a desired site; (d) deploying the implant at the desiredsite, whereby the implant expands to a size and shape substantiallysimilar to its size and shape before step (a); and (e) withdrawing thedelivery instrument.
 14. The method of claim 13, wherein the deliveryinstrument is a cannular, trocar, catheter, or a minimally invasiverigid or flexible instrument.
 15. The method of claim 14, wherein theminimally invasive instrument incorporates visualization orelectromechanics.
 16. The method of claim 15, wherein the minimallyinvasive instrument has a fiberoptic guide.
 17. The method of claim 14,wherein the minimally invasive instrument is a cystoscope, laproscope,arthroscope, or endoscope.
 18. The method of claim 13, wherein thedesired delivery site is the patient's bladder and the deliveryinstrument is advanced through the patient's urethra.
 19. A method oftreating a patient, which comprises the steps of: (a) collapsing and/orcompressing an implant of claim 1 or 2; (b) inserting the implant fromstep (a) into a rigid or flexible delivery instrument having a distaltip; (c) advancing the delivery instrument distal tip to a desired site;(d) deploying the implant at the desired site whereby the implantexpands to a size and shape substantially similar to its size and shapebefore step (a); (e) withdrawing the delivery instrument; and (f)leaving the implant in place for a desired period of time.
 20. Themethod of claim 19, which also comprises the steps of: (g) advancing thedistal tip of a removal instrument to the desired site; (h) engaging theimplant; and (i) withdrawing the implant and the removal instrument fromthe patient.
 21. The method of claim 19, wherein the delivery instrumentis a cannular, trocar, catheter, or a minimally invasive rigid orflexible instrument.
 22. The method of claim 21, wherein the minimallyinvasive instrument incorporates visualization or electromechanics. 23.The method of claim 22, wherein the minimally invasive instrument has afiberoptic guide.
 24. The method of claim 21, wherein the minimallyinvasive instrument is a cystoscope, laproscope, arthroscope, orendoscope.
 25. The method of claim 20, wherein the removal instrument isa cannular, trocar, catheter, or a minimally invasive rigid or flexibleinstrument.
 26. The method of claim 25, wherein the minimally invasiveinstrument incorporates visualization or electromechanics.
 27. Themethod of claim 26, wherein the minimally invasive instrument has afiberoptic guide.
 28. The method of claim 25, wherein the minimallyinvasive instrument is a cystoscope, laproscope, arthroscope, orendoscope.
 29. A method of systemically or locally treating a patient,which comprises the steps of: (a) positioning an implant of claim 1 or 2at a desired site within a patient; and (b) leaving the implant at thedesired site for a suitable period of time.
 30. A system for treating apatient, which comprises an implant of claim 1 or 2 and a deliveryinstrument.
 31. The system of claim 30, wherein the delivery instrumentis a cannular, trocar, catheter, or a minimally invasive rigid orflexible instrument.
 32. The system of claim 31, wherein the minimallyinvasive instrument incorporates visualization or electromechanics. 33.The system of claim 32, wherein the minimally invasive instrument has afiberoptic guide.
 34. The system of claim 31, wherein the minimallyinvasive instrument is a cystoscope, laproscope, arthroscope, orendoscope.
 35. The system of claim 30 which also comprises a removalinstrument.
 36. The system of claim 35, wherein the removal instrumentis a cannular, trocar, catheter, or a minimally invasive rigid orflexible instrument.
 37. The system of claim 36, wherein the minimallyinvasive instrument incorporates visualization or electromechanics. 38.The system of claim 37, wherein the minimally invasive instrument has afiberoptic guide.
 39. The method of claim 36, wherein the minimallyinvasive instrument is a cystoscope, laproscope, arthroscope, orendoscope.
 40. A method of treating a local urological condition in apatient, which comprises the steps of: (a) collapsing and/or compressingan implant of claim 1 or 2; (b) inserting the implant from step (a) intoa rigid or flexible delivery instrument having a distal tip; (c)advancing the delivery instrument distal tip through the patient'surethra to the bladder; (d) deploying the implant in the bladder wherebythe implant expands to a size and shape substantially similar to itssize and shape before step (a); (e) withdrawing the delivery instrument;and (f) leaving the implant in place in the bladder for a desired periodof time.
 41. The method of claim 40, wherein the local condition to betreated is cancer, an infection, an inflammation, a neurologicalcondition, or a trauma,
 42. A method of treating a condition in apatient that is systemic or external to the bladder, which comprises thesteps of: (a) collapsing and/or compressing an implant of claim 1 or 2,wherein the implant or the coating thereon comprises a solubilizer; (b)inserting the implant from step (a) into a rigid or flexible deliveryinstrument having a distal tip; (c) advancing the delivery instrumentdistal tip through the patient's urethra to the bladder; (d) deployingthe implant in the bladder whereby the implant expands to a size andshape substantially similar to its size and shape before step (a); (e)withdrawing the delivery instrument; and (e) leaving the implant inplace in the bladder for a desired period of time.
 43. The method ofclaim 42, wherein the condition to be treated is cancer, an infection,an inflammation, a neurological condition, or osteomylitis.
 44. Atherapeutic agent delivery implant for implantation to a mammalian site,the implant comprising: a resilient or flexible,hydrophobic supportreticulated elastomeric scaffold and at least one therapeutic agentsecured to and supported by the scaffold for release at the mammaliansite, wherein the therapeutic agent delivery implant is insertable intoa mammalian bladder or other suitable site via the urethra and islocatable within the bladder.
 45. The implant of claim 44, wherein theimplant is capable of being kept out of stimulative contact with thetrigone during the normal daily host routine.
 46. The implant of claim44, wherein the therapeutic agent delivery implant remains stable andfixed against the mucous membrane of the bladder away from the trigone.47. The implant of claim 44, wherein the therapeutic agent deliveryimplant is locatable in the dome of the bladder and permits flow ofurine through the therapeutic agent delivery implant material.
 48. Theimplant of claim 44, wherein the therapeutic agent delivery implant isshaped to engage and lodge against the bladder inner wall.
 49. Theimplant of claim 44, wherein the therapeutic agent delivery implant isconfigured, sized and prestressed to have a cross-sectional area inexcess of the anticipated maximum cross-sectional area of the intendedrecipient bladder.
 50. The implant of claim 44, wherein the therapeuticagent delivery implant is elastically compressible.
 51. A method ofdelivering an implant to a mammalian site comprising the steps of: (a)collapsing and/or loading into a delivery instrument a resilientlycompressible therapeutic agent delivery implant having an expandedconfiguration when deployed; (b) advancing the delivery instrumentthrough a mammalian urethra to access the bladder; (c) deploying thetherapeutic agent delivery implant through the delivery instrument intothe bladder; and (d) withdrawing the delivery instrument, leaving thetherapeatic agent delivery implant in the bladder.
 52. The method ofclaim 51, wherein the therapeutic agent delivery implant can be pulledinto a removal instrument, insertable into the urethra, and the methodfurther comprising the steps of: (e) advancing the removal instrumentinto the urethra and (f) removing the therapeutic agent delivery implantfrom the bladder with the removal instrument.
 53. The method of claim 51or 52, wherein the delivery instrument and the removal instrument areeach a cannular, trocar, catheter, or a minimally invasive rigid orflexible instrument.
 54. The method of claim 53, wherein the minimallyinvasive instrument incorporates visualization or electromechanics. 55.The method of claim 54, wherein the minimally invasive instrument has afiberoptic guide.
 56. The method of claim 53, wherein the minimallyinvasive instrument is a cystoscope, laproscope, arthroscope, orendoscope.
 57. The method of claim 52, wherein a gripping implement,deployed through the removal instrument grips the therapeutic agentdelivery implant and draws it into the removal instrument.
 58. Themethod of claim 57, wherein the gripping implement comprises a forcepsor hook.
 59. The method of claim 52, wherein removal is effected withinfrom one to twenty-eight days after insertion.